S100A proteins in propagation of a calcium signal in norm and pathology
ABSTRACT
Anna Cmoch1,*
alcium ions are essential factors controlling the balance between cell survival, growth,
Cdifferentiation and metabolism. Ca2+ acts as a global second messenger involved in the
regulation of all aspects of cell function. Fluctuations in the intra- and extracellular Ca2+ con- Patrick Groves2
centration [Ca2+] in response to different environmental stimuli drive most cellular func-
tions. Therefore, sustenance of calcium homeostasis requires perfect organization in time
Małgorzata Palczewska2
and space that is achieved by calcium binding proteins (CaBPs). These proteins are involved
in sensing and transforming calcium signals to downstream cellular responses. Growing
Sławomir Pikuła1
number of evidence suggests than many human disorders, including cancer progression, are
related to deregulation of cellular calcium homeostasis and defects in CaBPs functions. In
this review we will focus on the roles of S100A proteins in intracellular and extracellular
1
Department of Biochemistry, Nencki Insti-
calcium signalling and homeostasis. The S100A subfamily is among the most distinctive of
tute of Experimental Biology, Polish Acad-
EF-hand CaBPs and are found exclusively in vertebrates. They are believed to have evolved
emy of Sciences, 02-093 Warsaw, Poland
to enable activation of specific biochemical pathways in parallel to the activity of Ca2+ sen-
2
Department of Biological Chemistry, Instituto
sors such as calmodulin and/or annexins. The importance of S100 proteins is underscored by
de Tecnologia Quimica e Biologica, Universi-
their deregulated expression in neurodegenerative and inflammatory disorders, myopathies
dade Nova de Lisboa, Av. da Republica, 2780-
and cancer. In addition, S100 proteins serve as diagnostic markers in the clinic and are under
157 Oeiras, Portugal
constant investigation. Their roles and the roles of the S100A protein partners in normal and
pathology will be also discussed.
*
Department of Biochemistry, Nencki Institute
of Experimental Biology, Polish Academy of
InTroduCTIon
Sciences, 3 Pasteura Street, 02-093 Warsaw,
Poland; e-mail: [e-mail]
The role of Ca2+ as a key and pivotal second messenger in cells depends largely
on a wide number of heterogeneous calcium binding proteins. The S100 family
Received: October 10, 2012
of proteins comprises 25, homologous, acidic calcium binding proteins with the
Accepted: October 29, 2012
EF-hand type (helix-loop-helix motif) calcium binding domain. The canonical
C-terminal calcium-binding EF- hand is common to all EF-hand proteins, whi-
Key words: S100, annexins, signal transduc-
le the N-terminal EF-hand is non-canonical. The N-terminal EF-hand exhibits a
tion, calcium ions, calcium binding proteins
different architecture with a specific 14 amino acid motif flanked by helices HI
and HII. This motif is characteristic for S100 proteins and therefore it is often cal- Abbreviations: AnxA  vertebrate annexin;
[Ca2+]  Ca2+ concentration; CaBPs  calcium
led  S100-specific or  pseudo EF-hand . S100 proteins are characterized by low
binding proteins; ER  endoplasmic reticulum
molecular weights (9 13 kDa as monomers). They possess broadly known abi-
lity to form oligomers (homodimers, heterodimers and oligomeric assemblies)
Acknowledgements: This work was sup-
and are characterized by tissue and cell-specific expression [1-4]. There is a great
ported by a grant N N401 140639 from the Pol-
diversification of the identified S100 proteins, but solely they are present only in
ish Ministry of Science and Higher Education
vertebrates. S100 genes were not found in such model organism as Arabidopsis and by Polish-Portugal Executive Program for
years 2011-2012 (project 760) sponsored by the
thaliana, Drosophila melanogaster, Caenorhabditis elegans or Saccharomyces cerevisiae.
Polish Ministry of Science and Higher Educa-
In evolutionary terms, the lowest organism reported thus far containing a pseu-
tion and by Portuguese Fundaçćo para a CiÄ™n-
do EF- hand protein closely related to S100A is a chondrichthye (dogfish Squalus
cia e a Tecnologia.
acanthias) [3]. The adopted nomenclature designates the S100 genes in the chro-
mosomal cluster 1q 21 as S100A followed by Arabic numbers (S100A1, S100A2
etc.). Several S100 proteins are present in human, but absent in rat and mouse
(S100A2, S100A12). There is also gene duplication (human S100A7) supporting
the hypothesis of the rapid evolution and expansion of the S100 family of pro-
teins [5].
S100A proteins possess ability to form higher complexes (homodimers, hete-
rodimers and oligomeric assemblies) and are characterized by tissue and cell-
-specific expression [3,4]. Up to date, several heterodimeric S100 proteins have
been reported: S100B forms heterodimers with S100A1, S100A6 and S100A11;
S100A1 with S100A4, S100P and S100A7 with S100A10. Noncovalent multimers
were observed for S100A12, S100A8 D A9, S100A4 and a Zn2+-dependent tetramer
for S100A2 [3].
The conformation, folding and oligomerization state of S100s are responsive
to their metal-binding properties and have a pivotal influence on their function.
S100 proteins exert their actions usually through Ca2+ binding, although Zn2+
and Cu2+ have also been shown to regulate their biological activity. Binding of
Postępy Biochemii 58 (4) 2012 429
Ca2+ affinity, whereas in S100A2 the opposite
effect was observed. On the other hand, Zn2+
and Ca2+ binding to some of S100 proteins
are both required for their interaction with
receptors such as RAGE (the receptor for ad-
vanced glycation end-products). The S100A5,
S100A12 and S100A13 binds Cu2+ at the same
sites to which Zn2+ binds [3].
InTrA- And EXTrACELLuLAr
PArTnErS oF S100A ProTEInS
Members of the S100 family of proteins, in
the calcium dependent or independent man-
ner, interact with a variety of target proteins
including enzymes, cytoskeletal subunits,
receptors, transcription factors and nucleic
acids. Several S100 proteins exhibit Ca2+-de-
pendent interactions with metabolic enzymes
(S100A1 with aldolase C), with cytoskeletal
proteins (S100A1 with tubulin or with DNA-
-binding proteins, S100A2 and S100A4 inte-
ract with p53) [15].
Figure 1. STRING 9.0 analysis of direct (physical) or indirect (functional) associations between human
annexins and S100s proteins. The lines represent the existence of the several types of evidence used in
predicting the associations (high confidence score 0.7). The interactions are shown in different colors:
S100 proteins are known to interact with
black is co-expression, dark blue is co-occurrence, purple is experimental evidence, light green is text
members of the other large family of cal-
mining.
cium binding proteins - annexins -(AnxA2
with S100A4, S100A6, S100A10 or S100A11
Ca2+ to S100s exposes hydrophobic sites, which enable them
and AnxA6 with S100B, S100A6, S100A11,
to interact with specific target proteins or membranes. Bin-
S100A1) to form complexes that exhibit biological activities
ding of the target protein in the presence of calcium often
[16-18] (Fig. 1).
results in an increase in calcium affinity of the S100 prote-
in as well [6-8]. Most S100 proteins are directly involved in
S100A10 interacts not only with AnxA2 but also with
intracellular calcium signal transduction, Ca buffering and
multiple proteins: serotonin receptor 5-HT1B, NaV1.8 so-
in Ca uptake and transport. At low cytosolic [Ca2+], as in
dium channel, TASK-1 potassium channel, ASIC-1 chan-
the resting state of the cell, S100 proteins possess a closed,
nels; TRPV5/TRPV6 channels, cytosolic phospholipase A2,
relatively hydrophilic conformation. During cell activation
BAD (Bcl2-antagonist of cell death), AHNAK (neuroblast
the cytosolic [Ca2+] increases due to Ca2+ influx via plasma
differentiation-associated protein), cathepsin B, plasmi-
membrane Ca2+ channels and exchangers or due to their
nogen activator, transglutaminase, S100A7, S100A8 [19].
release from intracellular Ca2+ stores such as endoplasmic
Many functional consequences of the interactions between
reticulum (ER) and mitochondria. S100 proteins are charac-
S100A10 and its partners have been reported. There is accu-
terized by affinites for Ca2+, e.g. in a range that allows them
mulating evidence that S100A10 interacts with a diverse set
to respond to changes of cytosolic [Ca2+] (with one exception
of target proteins and regulates various biological functions
of S100A10, which is Ca2+ insensitive) [9-11]. The resulting,
in different cellular compartments.
Ca2+-dependent structural changes largely affect helix III
[12,13].
Most researchers concentrate on S100A10-annexin A2
Intracellularly, S100 proteins act as Ca2+ sensors, transla- heterotetramer formation and functions inside and outside
ting increases of cytosolic Ca2+ level into a cellular respon- of the cell. Typically, S100A10 is found in most cells bound
se. S100 proteins display a relatively large range of calcium to its annexin A2 ligand as the heterotetrameric S100A-
binding affinity (KD 20 500 µM). The binding of S100 pro- 102AnxA22 complex, AIIt. In addition to an intracellular di-
teins to their targets is typically calcium-dependent, but stribution, S100A10 is present on the extracellular surface
calcium-independent interactions have also been described of many cells. It was indicated that it facilitates the translo-
(S100A10-AnxA2). Evidence exists that Ca2+ binding dicta- cation of TRPV5 and TRPV6 channels towards the plasma
tes the membrane binding affinity of S100A. Interestingly, membrane in endothelial cells [20]. TRP (transient recep-
in some cases the interaction with membranes is weaker for tor potential) channels constitute a superfamily of sensory
Ca2+ bound S100A13 than in apo-S100A13 [14]. channels whose functions range from phototransduction
(where they were first described), olfaction, heat, cold sen-
S100A2, S100A3, S100A6, S100A7, S100A8D 9 and S100A12 sation etc., to Ca2+ sensors/transporters. The TRP Ca2+ chan-
bind Zn2+ in specific structural sites. The binding of diffe- nels are important for absorption of Ca2+ into kidney, bone,
rent metal ions results in conformational adjustments and placenta, or intestine to maintain systemic Ca2+ homeostasis.
modulation of S100 protein folding and function in cells. The S100A10-annexin 2 complex specifically associates with
In the case of S100A12, Zn2+ binding leads to an increase in the C-terminal of TRP channels and is suggested to play a
430 www.postepybiochemii.pl
role in guiding and localizing channels to the plasma mem-
brane and/or in the modulation of channel activity. It ap-
pears to act as a scaffolding protein that conjugates appro-
priate proteins at the plasma membrane. S100A10-annexin 2
also interacts with acid-sensing ion channels (ASIC1a) [21].
S100A10 has been reported to modulate the activity of
NaV1.8 (tetrodotoxin-resistant voltage-gated sodium chan-
nel), which is involved in the transmission of nociceptive
information from sensory neurons to the central nervous
system in nociceptive and neuropathic pain conditions.
NaV1.8 requires S100A10 accessory proteins for its functio-
nal expression on the plasma membrane [22].
The AnxA2-S100A10 complex formation in some types of
cells leads to plasminogen activation, either tissue-type pla-
sminogen activator (tPA) or urokinase-type plasminogen
activator (uPA), facilitating the conversion of plasminogen
to plasmin. The formation of a ternary complex between
tPA, plasminogen, and S100A10 provides a mechanism to
localize the proteolytic activity of plasmin to the cell sur-
Figure 2. Molecular mechanisms of S100 target protein interactions. In the presen-
face. Active plasmin both degrades fibrin directly and ac-
ce of elevated Ca2+ concentrations, apo-S100 undergoes a conformational change
tivates members of the matrix metalloproteases family,
and interacts with target proteins in a Ca2+-dependent pathway. The interaction
of S100A1 and RyR receptors is shown as a specific example. In contrast, S100A10
creating a localized proteolytic hub during angiogenesis or
interacts with annexin A2 independently of Ca2+.
tumor growth [23,24]. Annexin A2 plays an important role
in plasminogen regulation by controlling the levels of extra-
cellular S100A10 and by acting as a plasmin reductase. The
Ca2+ concentrations and enhances Ca2+ release in skeletal
mechanism by which annexin A2 regulates the extracellular
and in cardiac muscle. S100A1 was shown to directly in-
levels of S100A10 is unknown.
teract with PKA and this complex appears to affect Ca2+
channels. At the molecular level, S100A1 was shown to
Some ion channels that are regulated by calmodulin
interact in a Ca2+-dependent manner with the cardiac iso-
may in fact be modulated by S100 proteins, either under
forms of RYR2 (ryanodine receptor, isoform 2) (Fig. 2) [30],
resting conditions or under special circumstances. Whether
SERCA2A (sarco/endoplasmic reticulum calcium ATPase,
the effect of S100 proteins is direct or indirect, knowledge
isoform 2A) [31], phospholamban (PLN), titin, and the mi-
of the molecular basis for calmodulin interactions with ion
tochondrial F1-ATP synthase in complex V of the respira-
channels may be helpful in discerning how S100 proteins
tory chain [5].
modulate ion channels, in particular since there may well
be a similarity in their mode of action [25]. Some K+, Na+, S100A proteins have been also intensively studied for
and Cl- channels are activated or modulated by intracellular their interaction with heat shock-regulated proteins. For
Ca2+ signals giving rise to the notion that Ca2+ binding pro- example, S100A6 mediates nuclear translocation of Sgt1
teins may play a role in regulating channel gating function. and its interaction with Hsp-90 [32,33]. S100A1 and S100A2
There is growing evidence for modulatory roles played by proteins regulate the Hsp-90 interaction with target proteins
the S100 proteins in the regulation of those types of chan- [34]. S100A1 is also known to be a component of the Hsp70/
nels. External binding of S100 proteins to ion channels has, Hsp90 multichaperone complex [35].
however, not been reported so far [26].
CELLuLAr FunCTIonS oF S100A ProTEInS
S100A4, the recently recognized novel binding partner of
AnxA2, manages various functions dependent on cellular A richness of possible targets for S100 proteins is in
compartmentalization. Intracellular S100A4 exists as a sym- accordance with their multiple functions. Therefore, S100
metric homodimer that facilitates the binding of its target proteins regulate a diverse array of cellular activities,
proteins (actin, nonmuscle myosin IIA and IIB, tropomy- including the differentiation [36] and apoptosis [37,38],
osin). Extracellular S100A4 interacts with AnxA2, MMP-13, motility, membrane cytoskeleton interactions and cyto-
RAGE or epidermal growth factor (EGF) receptor ligands. skeleton dynamics [39,40], cellular Ca2+ homeostasis [41],
Through these interactions, S100A4 regulates cell mobility, transduction of intracellular Ca2+ signals, innate and ada-
invasion, and angiogenesis [27,28]. S100A4 was reported ptive immunity [1,2,25,42] and are predicted to partici-
as involved in the regulation of osteoblastic transcription pate in mineralization [43]. Up to now, only S100A4 and
factors Runx2/Cbfa1 and Osx. S100A4 plays an important S100A8/A9 have been considered as factors involved in
role in matrix remodeling by up-regulating the expression mineralization control [44-46]. They have been also re-
of crucial matrix metalloproteinases (MMPs) of bones [29]. ported as cellular protectors from oxidative cell damage,
regulators of protein phosphorylation [47], secretion and
S100A1 is known to increase the L-type Ca2+ channel (L- transcriptional factors [1-3]. S100A8/A9 complex, was re-
-type Ca2+ channels located in the SR) current at nanomolar ported as a Ca2+ sensor which controls the interplay be-
Postępy Biochemii 58 (4) 2012 431
Figure 3. Native states and oligomerization pathways in S100 proteins. A scheme
outlining possible routes of oligomerization pathways for S100A8 and S100A9
proteins. From Fritz et al. [3], modified.
tween extracellular Ca2+ entry and intraphagosomal ROS
production [48].
Figure 4. Binding of S100A to receptors in human disorders. Activation of RAGE
by S100 proteins leads to cell survival and proliferation. S100A8/A9 complex ac-
tivates TLR-4 receptors to induce inflammation. S100A8/A9 and S100A12 interact
Within the cells, S100 proteins often translocate from
with scavenger receptor. From LeClerc et al. [4], modified
one compartment to another (nucleus, cytoplasm) in re-
sponse to changes in calcium concentration or concentra-
and vascular smooth muscle cells, neurons, astrocytes,
tion of extracellular S100 using different translocation pa-
Schwann cells, epithelial cells, myoblasts and cardiomy-
thways. In addition to their intracellular functions, S100
ocytes [49]. Multimeric assemblies seem to be necessary for
proteins can also be secreted and may exert the role of
the extracellular functions of S100 proteins and have been
cytokines (e.g. S100A4, S100A8, S100A9) through the ac-
reported for S100A12, S100A4, S100B and S100A8/A9 [3].
tivation of various cell surface receptors in an autocrine
S100-associated cell signalling may be promiscuous. This
and paracrine manner through various receptors RAGE
can be best exemplified through S100A8 D A9, which pro-
(Fig. 3), toll-like receptor 4 (TLR-4) (Fig. 4), G-protein-co-
motes RAGE-dependent cell survival as well as multiple
upled receptors, scavenger receptors or heparan sulfate
RAGE-independent cell death pathways.
proteoglycans and N-glycans [25]. S100B, S100P, S100A4,
S100A6, S100A8/A9, S100A11 and S100A12 are known to This diversity in function of the S100 provides evidence
interact with RAGE [49], while S100A8/A9 also bind Toll- of very extensive evolutionary optimization of the fit be-
-like receptors or TLRs [50]. Some S100 proteins, including tween the EF-hand CaBPs fold and the calcium ion. S100
S100A4, S100A7, S100A8 D A9, S100A11, S100A12, S100B proteins form a phylogenetically young group among the
and others, are commonly secreted, exhibiting cytokine- EF-hand proteins (present only in verterbrates). Future rese-
-like and chemotactic activity. When S100A7, S100A8, arch in the coming years will certainly contribute to clarify
S100A9, S100A12 or S100B are secreted in response to cell some of these and other questions and will ultimately bring
damage or activation, they act as alarmins (cellular stress us to a higher level of understanding the biology of tumour
signals), activating other immune and endothelial cells. and degeneration and enable to use our acquired knowled-
Frequently, S100 poroteins are secreted upon Ca2+ signa- ge of S100 structure and functions in developing strategies
ling via vesicle fusion with the cell membrane into the to modulate their activity for therapeutic purposes [51].
extra cellular space, where they might acquire oligomeric
rEGuLATIon oF S100A FunCTIonS BY
structures specialized for extracellular functions [5].
PoSTTrAnSLATIonAL ModIFICATIonS
S100 proteins can also be released into the extracellular
space in response to stimuli, or during cell damage, and A number of posttranslational protein modifications have
they promote responses including neuronal survival and been described. Posttranslational protein modifications may
extension (S100B), apoptosis (S100A4 and S100A6), inflam- result in physiochemical changes of the protein with respect
mation (S100B, S100A8/A9, S100A11 and S100A12), au- to mass, charge, structure and conformation. S100 proteins
toimmunity (S100A8/A9), chemotaxis (S100A8/A9) and may be modified by various post-translational modifica-
cell proliferation and survival (S100P, S100A7), effectively tions, including phosphorylation, methylation, acetylation,
functioning as paracrine and autocrine mediators. Thus, and oxidation. These modifications may alter their ion-bin-
extracellular S100 proteins exert regulatory activities on ding properties, interactions with target proteins, transloca-
monocytes/macrophages/microglia, neutrophils, lym- tion within cell compartments, degradation, protein-protein
phocytes, mast cells, articular chondrocytes, endothelial interactions and extracellular functions.
432 www.postepybiochemii.pl
Figure 5. Intracellular and extracellular roles of S100A proteins. Shown are the best known targets/activities putatively regulated by S100A proteins in a Ca2+-dependent
and Ca2+-independent manner. From Donato et al. [1], modified.
S100 proteins can be modified post-translationally by Sumoylation of two lysines in S100A4 molecule results in
phosphorylation (S100A8/A9, S100A11), nitrosylation nuclear translocation of this protein and its action as trans-
(S100A1, S100B, S100A8), citrullination (S100A3) (34), car- cription factor bound to the promoter region of MMP-13
boxymethylation (S100A8/A9), glutathionylation, trans- [29,53]. Up to date S100 proteins have not been described to
amidation (S100A11) or sumoylation. These modifications be glycosylated.
often modulate the interaction with calcium or target pro-
dErEGuLATIon oF S100A GEnES EXPrESSIon
teins. Additionally, the promoters of several S100 proteins
have been found hypo- or hyper-methylated, resulting in
epigenetic changes in protein expression [25] (Fig. 5). Deregulated expression of genes encoding members of
the S100 family of calcium-binding proteins has been asso-
Extracellular functions of several S100s may be regula- ciated with multiple tumor types. S100A2, S100A4, S100A6
ted by oxidative modifications. Many redox-based signa- and S100A10 genes alterations have been associated with
ling pathways are regulated by reversible modifications brain tumors. Furthmore, the methylation/demethylation
such as intra- and interprotein disulfides, S-nitrosylation of these genes plays a role in the control of their tumor gene-
and glutathionylation. Cysteine S-nitrosylation is a new fac- rating potency [56]. S100A1 is thought to modulate the Ca2+
tor responsible for increasing functional diversity of S100A sensitivity of the sarcoplasmic reticulum (SR) Ca2+ release
proteins and helps explain the role of S100A as a Ca2+ si- channels (ryanodine receptors or RyRs) and chronic absence
gnal transmitter sensitive to NOS/redox state within cells. of S100A1 results in enhanced L-type Ca2+ channel activity
S100A1 has been recently reported in PC12 cells to be endo- combined with a blunted SR Ca2+ release amplification in
genously S-nitrosylated at site important for target binding cardiomyocytes [57]. The loss of S100A10 from the extracel-
[52]. S100A8 and S100A9 are S-nitrosylated by NO donors lular surface of cancer cells results in a significant loss in
including GSNO, the physiological regulator of NO trans- plasmin generation. In addition, S100A10 knock-down cells
port and signaling. S100A8 is preferentially nitrosylated in demonstrate a dramatic loss in extracellular matrix degra-
the S100A8/A9 complex. S-nitrosylation of S100A9 is cal- dation and invasiveness as well as reduced metastasis [58].
cium-dependent, whereas S100A8 is not. In contrast to the The specific knockdown of S100A4 strongly suppressed cell
proposed, protective role of extracellular S100A8 and to growth, migration and invasion activities in cancer cells,
some extent, S100A9, these proteins regulate intracellular therefore S100A4 may positively regulate tumor cell proli-
NADPH oxidase activity and thus, ROS (reactive oxygen feration, invasion and metastasis associated with multiple
species) generation. Thus, there is a paradigm on dual roles molecules [59].
of S100A8/A9 in redox balance. Oxidation may represent a
switch, whereby the modified proteins display their func- S100A ProTEInS In HuMAn dISEASES
 CLInICAL SIGnIFICAnCE
tions [53].
Phosphorylation of Ser and Thr residues increased the af- Members of the S100 protein family have been shown to
finity of S100A for the p53 TAD domains. Conversely, acety- posess pathophysiologic implications. In addition, members
lation and phosphorylation of the C-terminus of p53 decre- of the S100 protein family are extensively tested as useful
ased the affinity for S100A2 [15]. S100A9 protein has been biomarkers of certain diseases and potential targets of clini-
also reported as phosphorylation target for MAPK [54]. cal therapies [60]. There is growing evidence that expression
Phosphorylation of that protein leads to S100A8/A9 hete- of S100 proteins is altered in pathologies. The S100 protein
rotetramer translocation and NOX2 activation. Kouno et al. levels are associated with a wide array of pathological con-
[55] proposed phosphorylated S100A11 to be recognized by ditions like chronic inflammation [1,2,61-65], immunode-
its target protein, nucleolin and in such complex transloca- fence [27], cardiomyopathies [30,66-68], atherosclerosis [69],
ted to the nucleus. rheumatoid arthritis [70,71], cystic fibrosis [72] and cancer
Postępy Biochemii 58 (4) 2012 433
[1,2,61,73-89]. S100 proteins are thought to be also associa- 10. Zimmer DB, Wright Sadosky P, Weber DJ (2003) Molecular mechani-
sms of S100-target protein interactions. Microsc Res Tech 60: 552-559
ted with diabetes and its complications [80], neurodege-
11. Santamaria-Kisiel L, Rintala-Dempsey AC, Shaw GS (2006) Calcium-
neration and Alzheimer disease [90,91] and posttraumatic
-dependent and -independent interactions of the S100 protein family.
stress disorder [92].One of the most intringuing directions
Biochem J 396: 201-214
in research on S100A proteins is their involvement in neuro-
12. Groves P, Finn BE, Kuznicki J, Forsén S (1998) A model for target pro-
nal plasticity regulation and depression [19].
tein binding to calcium-activated S100 dimers. FEBS Lett 421: 175-179
Functions of some S100A proteins in cancer progression
13. Smith SP, Shaw GS (1998) A change-in-hand mechanism for S100 si-
are opposite to others, for example down-regulation of gnalling. Biochem Cell Biol 76: 324-333
S100A6 and S100A10 in breast cancer, irrespective of patho- 14. Kathir KM, Ibrahim K, Rajalingam D, Prudovsky I, Yu C, Kumar TK
(2007) S100A13-lipid interactions-role in the non-classical release of the
logical stage, was observed whereas S100A7, S100A8 and
acidic fibroblast growth factor. Biochim Biophys Acta 1768: 3080-3089
S100A9 were strongly up-regulated only in some type of
15. Van Dieck J, Teufel DP, Jaulent AM, Fernandez-Fernandez MR, Ru-
breast cancer [93]. There are many factors that can modu-
therford TJ, Wyslouch-Cieszynska A, Fersht AR (2009) Posttranslatio-
late S100A expression in biological systems. For example,
nal modifications affect the interaction of S100 proteins with tumor
the S100A10 coding gene is regulated by various factors:
suppressor p53. J Mol Biol 394: 922-930
dexamethasone, TGF-Ä…, EGF, NO donors, interferon-Å‚, vita-
16. Miwa N, Uebi T, Kawamura S (2008) S100-annexin complexes - biolo-
min D, retinoic acid, NGF, electroconvulsive treatment [19].
gy of conditional association. FEBS J 275: 4945-4955
Up regulation of S100A10 occurs also in response to AnxA2
17. Rintala-Dempsey AC, Rezvanpour A, Shaw GS (2008) S100-annexin
upregulation. Down-regulation of AnxA2 is coordinated
complexes - structural insights. FEBS J 275: 4956-4966
with lack of S100A10 protein, but the specificity of mecha-
18. Rezvanpour A, Santamaria-Kisiel L, Shaw GS (2011) The S100A10-an-
nism which is responsible for that phenomenon still rema-
nexin A2 complex provides a novel asymmetric platform for membra-
ins unknown. Here we provided the examples of complica- ne repair. J Biol Chem 286: 40174-40183
ted regulation of S100A proteins functions and expression.
19. Svenningsson P, Greengard P (2007) p11 (S100A10) - an inducible ada-
ptor protein that modulates neuronal functions. Curr Opin Pharmacol
7: 27-32
ConCLudInG rEMArKS And FuTurE PErSPECTIVES
20. Van de Graaf SJ, Hoenderop JGJ, Bindels RJM (2006) Regulation of
TRPV5 and TRPV6 by associated proteins. Am J Physiol Renal Physiol
The thesis is emerging that S100 proteins are phyloge-
290: F1295-F1302
netically new proteins displaying the unusual property of
21. Donier E, Rugiero F, Okuse K, Wood JN (2005) Annexin II light chain
acting both within cells as Ca2+ sensor proteins implicated
p11 promotes functional expression of acid-sensing ion channel ASI-
in Ca2 +signal transduction, and outside cells as ligands for
C1a. J Biol Chem 280: 38666-38672
specific cell surface receptors on an increasingly larger num-
22. Swanwick RS, Pristerá A, Okuse K (2010) The trafficking of Na(V)1.8.
ber of cell types. Therefore the grand challenge ahead is de-
Neurosci Lett 486: 78-83
termining the role of particular S100A proteins in diseases
23. O Connell PA, Surette AP, Liwski RS, Svenningsson P, Waisman DM
related to Ca2+ homeostasis disorder such as neurological
(2010) S100A10 regulates plasminogen-dependent macrophage inva-
diseases and artheriosclerosis.
sion. Blood 116: 1136-1146
24. Phipps KD, Surette AP, O Connell PA, Waisman DM (2011) Plasmino-
LITErATurE gen receptor S100A10 Is essential for the migration of tumor-promo-
ting macrophages into tumor sites. Cancer Res 71: 6676-6683
1. Donato R (2001) S100: a multigenic family of calcium-modulated pro-
teins of the EF-hand type with intracellular and extracellular functio- 25. Hermann A, Donato R, Weiger TM, Chazin WJ (2012) S100 calcium
nal roles. Int J Biochem Cell Biol 33: 637-668
binding proteins and ion channels. Front Pharmacol 3: 67
2. Heizmann CW, Fritz G, Schäfer BW (2002) S100 proteins: structure, 26. Chazin WJ (2011) Relating form and function of EF-hand calcium bin-
functions and pathology. Front Biosci 7: 1356-1368 ding proteins. Acc Chem Res 44: 171-179
3. Fritz G, Botelho HM, Morozova-Roche LA, Gomes CM (2010) Natural 27. Bian L, Strzyz P, Jonsson IM, Erlandsson M, Hellvard A, Brisslert
and amyloid self-assembly of S100 proteins: structural basis of functio- M, Ohlsson C, Ambartsumian N, Grigorian M, Bokarewa M (2011)
nal diversity. FEBS J 277: 4578-4590 S100A4 deficiency is associated with efficient bacterial clearance and
protects against joint destruction during staphylococcal infection. J In-
4. Leclerc E, Heizmann CW (2011) The importance of Ca2+/Zn2+ signa-
fect Dis 204: 722-730
ling S100 proteins and RAGE in translational medicine. Front Biosci
3: 1232-1262
28. Semov A, Moreno MJ, Onichtchenko A, Abulrob A, Ball M, Ekiel I,
Pietrzynski G, Stanimirovic D, Alakhov V (2005) Metastasis-associated
5. Schaub MC, Heizmann CW (2008) Calcium, troponin, calmodulin,
protein S100A4 induces angiogenesis through interaction with anne-
S100 proteins: from myocardial basics to new therapeutic strategies.
xin II and accelerated plasmin formation. J Biol Chem 280: 20833-20841
Biochem Biophys Res Commun 369: 247-264
29. Miranda KJ, Loeser RF, Yammani RR (2010) Sumoylation and nuclear
6. Bhattacharya S, Bunick CG, Chazin WJ (2004) Target selectivity in EF-
translocation of S100A4 regulate IL-1beta-mediated production of ma-
-hand calcium binding proteins. Biochim Biophys Acta 1742: 69-79
trix metalloproteinase-13. J Biol Chem 285: 31517-31524
7. Streicher WW, Lopez MM, Makhatadze GI (2009) Annexin I and an-
30. Prosser BL, Hernández-Ochoa EO, Schneider MF (2011) S100A1 and
nexin II N-terminal peptides binding to S100 protein family members:
calmodulin regulation of ryanodine receptor in striated muscle. Cell
specificity and thermodynamic characterization. Biochemistry 48:
Calcium 50: 323-331
2788-2798
31. Kranias EG, Hajjar RJ (2012) Modulation of cardiac contractility by the
8. Streicher WW, Lopez MM, Makhatadze GI (2010) Modulation of qu-
hospholamban/SERCA2a regulatome. Circ Res 110: 1646-1660
aternary structure of S100 proteins by calcium ions. Biophys Chem
151: 181-186 32. Filipek A, Michowski W, Kuznicki J (2007) Involvement of S100A6
(calcyclin) and its binding partners in intracellular signaling path-
9. Otterbein LR, Kordowska J, Witte-Hoffmann C, Wang CLA, Domin-
guez R (2002) Crystal structures of S100A6 in the Ca2+-free and Ca2+- ways. Advan Enzyme Regul 48: 225-239
-bound states: The calcium sensor mechanism of S100 proteins reve- 33. Prus W, Filipek A (2011) S100A6 mediates nuclear translocation of
aled at atomic resolution structure. Structure 10: 557-567 Sgt1: a heat shock-regulated protein. Amino Acids 41: 781-787
434 www.postepybiochemii.pl
34. Shimamoto S, Kubota Y, Tokumitsu H, Kobayashi R (2010) S100 pro- expression and phosphorylation of the two S100A9 isoforms in mono-
teins regulate the interaction of Hsp90 with cyclophilin 40 and FKBP52 nuclear cells from patients with systemic lupus erythematosus: a
through their tetratricopeptide repeats. FEBS Lett 584: 1119-1125 proteomic signature for circulating low-density granulocytes. J Pro-
teomics 75: 1778-1791
35. Okada M, Hatakeyama T, Itoh H, Tokuta N, Tokumitsu H, Kobayashi
R (2004) S100A1 is a novel molecular chaperone and a member of the 55. Kouno T, Mizuguchi M, Sakaguchi M, Makino E, Mori Y, Shinoda H,
Hsp70/Hsp90 multichaperone complex. J Biol Chem 279: 4221-4233 Aizawa T, Demura M, Huh NH, Kawano K (2008) The structure of
S100A11 fragment explains a local structural change induced by phos-
36. Kizawa K, Takahara H, Unno M, Heizmann CW (2011) S100 and S100
phorylation. J Pept Sci 14: 1129-1138
fused-type protein families in epidermal maturation with special focus
on S100A3 in mammalian hair cuticles. Biochimie 93: 2038-2047 56. Lindsey JC, Lusher ME, Anderton JA, Gilbertson RJ, Ellison DW, Clif-
ford SC (2007) Epigenetic deregulation of multiple S100 gene fam-
37. Li C, Chen H, Ding F, Zhang Y, Luo A, Wang M, Liu Z (2009) A novel
ily members by differential hypomethylation and hypermethylation
p53 target gene, S100A9, induces p53-dependent cellular apoptosis
events in medulloblastoma. Br J Cancer 97: 267-274
and mediates the p53 apoptosis pathway. Biochem J 422: 363-372
57. Gusev K, Ackermann GE, Heizmann CW, Niggli E (2009) Ca2+ signa-
38. Atallah M, Krispin A, Trahtemberg U, Ben-Hamron S, Grau A, Ver-
ling in mouse cardiomyocytes with ablated S100A1 protein. Gen Phy-
bovetski I, Mevorach D (2012) Constitutive neutrophil apoptosis: reg-
siol Biophys 28: 371-383
ulation by cell concentration via S100 A8/9 and the MEK-ERK path-
way. PLoS One 7: e29333 58. Kwon M, MacLeod TJ, Zhang Y, Waisman DM (2005) S100A10, an-
nexin A2, and annexin A2 heterotetramer as candidate plasminogen
39. Benaud C, Gentil BJ, Assard N, Court M, Garin J, Delphin C, Baudier
receptors. Front Biosci 10: 300-325
J (2004) AHNAK interaction with the annexin 2/S100A10 complex
regulates cell membrane cytoarchitecture. J Cell Biol 164: 133-144 59. Huang L, Xu Y, Cai G, Guan Z, Cai S (2012) Downregulation of S100A4
expression by RNA interference suppresses cell growth and invasion
40. Jung MJ, Murzik U, Wehder L, Hemmerich P, Melle C (2010) Regula-
in human colorectal cancer cells. Oncol Rep 27: 917-922
tion of cellular actin architecture by S100A10. Exp Cell Res 316: 1234-
1240 60. Sedaghat F, Notopoulos A (2008) S100 protein family and its applica-
tion in clinical practice. Hippokratia 12: 198-204
41. Donato R (2003) Intracellular and extracellular roles of S100 proteins.
Microsc Res Tech 60: 540-551 61. Srikrishna G, Freeze HH (2009) Endogenous damage-associated mole-
cular pattern molecules at the crossroads of inflammation and cancer.
42. Woodham AW, Da Silva DM, Skeate JG, Raff AB, Ambroso MR, Brand
Neoplasia 11: 615-628
HE, Isas JM, Langen R, Kast WM (2012) The S100A10 subunit of the
annexin A2 heterotetramer facilitates L2-mediated human Papilloma- 62. Goyette J, Geczy CL (2011) Inflammation-associated S100 proteins:
virus infection. PLoS One 7: e43519 new mechanisms that regulate function. Amino Acids 41: 821-842
43. Cmoch A, Strzelecka-Kiliszek A, Palczewska M, Groves P, Pikula S 63. Lim SY, Raftery MJ, Geczy CL (2011) Oxidative modifications of
(2011) Matrix vesicles isolated from mineralization-competent Saos-2 DAMPs suppress inflammation: the case for S100A8 and S100A9. An-
cells are selectively enriched with annexins and S100 proteins. Bio- tioxid Redox Signal 15: 2235-2248
chem Biophys Res Commun 412: 683-687
64. Meijer B, Gearry RB, Day AS (2012) The role of S100A12 as a systemic
44. Duarte WR, Shibata T, Takenaga K, Takahashi E, Kubota K, Ohya K, marker of inflammation. Int J Inflam, in press
Ishikawa I, Yamauchi M, Kasugai S (2003) S100A4: A novel negative
65. Nasser MW, Qamri Z, Deol YS, Ravi J, Powell CA, Trikha P, Schwen-
regulator of mineralization and osteoblast differentiation. J Bone Min-
dener RA, Bai XF, Shilo K, Zou X, Leone G, Wolf R, Yuspa SH, Ganju
er Res 18: 493-501
RK (2012) S100A7 enhances mammary tumorigenesis through upre-
45. McCormick MM, Rahimi F, Bobryshev YV, Gaus K, Zreiqat H, Cai gulation of inflammatory pathways. Cancer Res 72: 604-615
H, Lord RSA, Geczy CL (2005) S100A8 and S100A9 in human arterial
66. Kraus C, Rohde D, Weidenhammer C, Qiu G, Pleger ST, Voelkers M,
wall, implications for artherogenesis. J Biol Chem 280: 41521-41529
Boerries M, Remppis A, Katus HA, Most P (2009) Kraus S100A1 in car-
46. Zreiqat H, Howlett CR, Gronthos S, Hume D, Geczy CL (2007) diovascular health and disease: closing the gap between basic science
S100A8/S100A9 and their association with cartilage and bone. J Mol and clinical therapy. J Mol Cell Cardiol 47: 445-455
Histol 38: 381-391
67. Rohde D, Ritterhoff J, Voelkers M, Katus HA, Parker TG, Most P (2010)
47. Yamaguchi F, Umeda Y, Shimamoto S, Tsuchiya M, Tokumitsu H, To- S100A1: a multifaceted therapeutic target in cardiovascular disease. J
kuda M, Kobayashi R (2012) A link between Ca2+ signal transduction Cardiovasc Transl Res 3: 525-537
and protein dephosphorylation. J Biol Chem 287: 13787-13798
68. Ritterhoff J, Most P (2012) Targeting S100A1 in heart failure. Gene Ther
48. Steinckwich N, Schenten V, Melchior C, Bréchard S, Tschirhart EJ 19: 613-621
(2011) An essential role of STIM1, Orai1, and S100A8-A9 proteins for
69. Abbas A, Aukrust P, Dahl TB, Bjerkeli V, Sagen EB, Michelsen A, Rus-
Ca2+ signaling and FcłR-mediated phagosomal oxidative activity. J
sell D, SÅ‚rensen KK, Holm S, Skjelland M, Halvorsen B (2012) High
Immunol 186: 2182-2191
levels of S100A12 are associated with recent plaque symptomatology
49. Leclerc E, Sturchler E, Vetter SW, Heizmann CW (2009) Crosstalk be- in patients with carotid atherosclerosis. Stroke 43: 1347-1353
tween calcium, amyloid beta and the receptor for advanced glycation
70. Grevers LC, de Vries TJ, Vogl T, Abdollahi-Roodsaz S, Sloetjes AW,
endproducts in Alzheimer s disease. Rev Neurosci 20: 95-110
Leenen PJM, Roth J, Everts V, van den Berg WB, van Lent PLE (2011)
50. Källberg E, Vogl T, Liberg D, Olsson A, Björk P, Wikström P, Bergh S100A8 enhances osteoclastic bone resorption in vitro through activa-
A, Roth J, Ivars F, Leanderson T (2012) S100A9 interaction with TLR4 tion of toll-like receptor 4. Implications for bone destruction in murine
promotes tumor growth. PLoS One 7: e34207 antigen-induced arthritis. Arthritis Rheum 63: 1365-1375
51. Rezvanpour A, Shaw GS (2009) Unique S100 target protein interac- 71. Nishioku T, Furusho K, Tomita A, Ohishi H, Dohgu S, Shuto H,
tions. Gen Physiol Biophys 28: F39-F46 Yamauchi A, Kataoka Y (2011) Potential role for S100A4 in the disrup-
tion of the blood-brain barrier in collagen-induced arthritic mice, an
52. Lenarcic Zivkovic M, Zareba-Koziol M, Zhukova L, Poznanski J,
animal model of rheumatoid arthritis. Neuroscience 189: 286-292
Zhukov I, Wyslouch-Cieszynska A (2012) Post-translational S-nitro-
sylation is an endogenous factor fine-tuning the properties of human 72. Borthwick LA, Riemen C, Goddard C, Colledge WH, Mehta A, Ger-
S100A1 protein. J Biol Chem, in press ke V, Muimo R (2008) Defective formation of PKA/CnA-dependent
annexin 2-S100A10/CFTR complex in"F508 cystic fibrosis cells. Cell
53. Lim SY, Raftery MJ, Goyette J, Hsu K, Geczy CL (2009) Oxidative mod-
Signal 20: 1073-1083
ifications of S100 proteins: functional regulation by redox. J Leukoc
Biol 86: 577-587 73. Emberley ED, Murphy LC, Watson PH (2004) S100 proteins and their
influence on pro-survival pathways in cancer. Biochem Cell Biol 82:
54. Pavón EJ, García-Rodríguez S, Zumaquero E, Perandrés-López R,
508-515
Rosal-Vela A, Lario A, Longobardo V, Carrascal M, Abián J, Callejas-
Rubio JL, Ortego-Centeno N, Zubiaur M, Sancho J (2012) Increased
Postępy Biochemii 58 (4) 2012 435
74. Wang G, Zhang S, Fernig DG, Martin-Fernandez M, Rudland PS, Bar- 84. Elsner M, Rauser S, Maier S, Schöne C, Balluff B, Meding S, Jung G,
raclough R (2005) Mutually antagonistic actions of S100A4 and S100A1 Nipp M, Sarioglu H, Maccarrone G, Aichler M, Feuchtinger A, Langer
on normal and metastatic phenotypes. Oncogene 24: 1445-1454 R, Jütting U, Feith M, Küster B, Ueffing M, Zitzelsberger H, Höfler H,
Walch A (2012) MALDI imaging mass spectrometry reveals COX7A2,
75. Rust R, Visser L, van der Leij J, Harms G, Blokzijl T, Deloulme JC,
TAGLN2 and S100-A10 as novel prognostic markers in Barrett s ad-
van der Vlies P, Kamps W, Kok K, Lim M, Poppema S, van den Berg
enocarcinoma. J Proteomics 75: 4693-4704
A (2005) High expression of calcium-binding proteins, S100A10,
S100A11 and CALM2 in anaplastic large cell lymphoma. Br J Haema- 85. Fleming JM, Ginsburg E, Oliver SD, Goldsmith P, Vonderhaar BK
tol 131: 596-608 (2012) Hornerin, an S100 family protein, is functional in breast cells
and aberrantly expressed in breast cancer. BMC Cancer 12: 266
76. Wang G, Wang X, Wang S, Song H, Sun H, Yuan W, Cao B, Bai J, Fu
S (2008) Colorectal cancer progression correlates with upregulation of 86. Grebhardt S, Veltkamp C, Ströbel P, Mayer D (2012) Hypoxia and
S100A11 expression in tumor tissues. Int J Colorectal Dis 23: 675-682 HIF-1 increase S100A8 and S100A9 expression in prostate cancer. Int
J Cancer, in press
77. Tsuna M, Kageyama S, Fukuoka J, Kitano H, Doki Y, Tezuka H, Ya-
suda H (2009) Significance of S100A4 as a prognostic marker of lung 87. Kahn N, Meister M, Eberhardt R, Muley T, Schnabel PA, Bender C, Jo-
squamous cell carcinoma. Anticancer Res 29: 2547-2554 hannes M, Keitel D, Sültmann H, Herth FJ, Kuner R (2012) Early detec-
tion of lung cancer by molecular markers in endobronchial epithelial-
78. Boye K, Maelandsmo GM (2010) S100A4 and metastasis: a small actor
lining fluid. J Thorac Oncol 7: 1001-1008
playing many roles. Am J Pathol 176: 528-535
88. Lukanidin E, Sleeman JP (2012) Building the niche; the role of the S100
79. Salama I, Malone PS, Mihaimeed F, Jones JL (2008) A review of the
proteins in metastatic growth. Semin Cancer Biol 22: 216-225
S100 proteins in cancer. Eur J Surg Oncol 34: 357-364
89. Nipp M, Elsner M, Balluff B, Meding S, Sarioglu H, Ueffing M, Rauser
80. Basso D, Greco E, Padoan A, Fogar P, Scorzeto M, Fadi E, Bozzato D,
S, Unger K, Höfler H, Walch A, Zitzelsberger H (2012) S100-A10, thio-
Moz S, Navaglia F, Zambon CF, Seraglia R, De Carlo E, Valerio A, Reg-
redoxin, and S100-A6 as biomarkers of papillary thyroid carcinoma
giani C, Pedrazzoli S, Plebani M (2011) Altered intracellular calcium
with lymph node metastasis identified by MALDI imaging. J Mol Med
fluxes in pancreatic cancer induced diabetes mellitus: relevance of the
(Berl) 90: 163-174
S100A8 N-terminal peptide (NT-S100A8). J Cell Physiol 226: 456-468
90. Chang K, Kim HJ, Suh JH (2012) The role of S100a9 in the pathogenesis
81. Fujiwara M, Kashima TG, Kunita A, Kii I, Komura D, Grigoriadis
of Alzheimer s disease: the therapeutic effects of S100A9 knockdown
AE, Kudo A, Aburatani H, Fukayama M (2011) Stable knockdown of
or knockout. Neurodegenerative Dis 10: 27-29
S100A4 suppresses cell migration and metastasis of osteosarcoma. Tu-
mor Biol 32: 611-622 91. Vogl T, Gharibyan AL, Morozova-Roche LA (2012) Pro-Inflammatory
S100A8 and S100A9 Proteins: self-assembly into multifunctional na-
82. Li J, Riau AK, Setiawan M, Mehta JS, Ti SE, Tong L, Tan DT, Beuer-
tive and amyloid complexes. Int J Mol Sci 13: 2893-2917
man RW (2011) S100A expression in normal corneal-limbal epithelial
cells and ocular surface squamous cell carcinoma tissue. Mol Vis 17: 92. Zhang L, Ursano RJ, Li H (2012) P11: a potential biomarker for post-
2263-2271 traumatic stress disorder. Methods Mol Biol 829: 453-468
83. Yang X, Popescu NC, Zimonjic DB (2011) DLC1 interaction with 93. Carlsson H, Petersson S, Enerbäck C (2005) Cluster analysis of S100
S100A10 mediates inhibition of in vitro cell invasion and tumorigenic- gene expression and genes correlating to psoriasin (S100A7) expres-
ity of lung cancer cells through a RhoGAP-independent mechanism. sion at different stages of breast cancer development. Int J Oncol 27:
Cancer Res 71: 2916-2925 1473-1481
udział białek S100A w przekazywaniu sygnału
wapniowego w normie i patologii
Anna Cmoch1,*, Patrick Groves2, Małgorzata Palczewska2, Sławomir Pikuła1
1
Zakład Biochemii, Instytut Biologii Doświadczalnej PAN im. M. Nenckiego, Warszawa, Polska
2
Zakład Chemii Biologicznej, Instytut Technologii Chemicznej i Biologicznej, Oeiras, Portugalia
*
e-mail: [e-mail]
Słowa kluczowe: białka S100, aneksyny, przekazywanie sygnałów, jony wapnia, białka wiążące wapń
STrESZCZEnIE
Jony wapnia są niezbędne w utrzymaniu równowagi pomiędzy procesami wzrostu, przeżywalności, różnicowania i metabolizmu komórki.
Jony wapnia odgrywajÄ… rolÄ™ przekaz
nika II rzędu w niemal wszystkich procesach komórkowych. Zmiany zewnątrz- i wewnątrzkomórkowe-
go stężenia jonów wapnia, w odpowiedzi na pobudzenie, wpływają na funkcje komórek. utrzymanie homeostazy wapnia wymaga właściwej
organizacji wewnątrzkomórkowego rozmieszczenia wapnia, w czym uczestniczą białka wiążące jony wapnia. Białka te przekształcają sygnał
wapniowy w odpowiedz
komórkową. Coraz większa liczba obserwacji świadczy o tym, że zaburzona homeostaza wapnia i nieprawidło-
wa funkcja białek wiążących jony wapnia jest przyczyną wielu chorób człowieka, w tym rozwoju nowotworów. W niniejszym artykule
przeglądowymi, omówiono funkcje białek S100A w procesie przekazywania sygnału wapniowego. Białka z tej rodziny występują tylko w
organizmach kręgowców. uczestniczą w specyficznych procesach komórkowych, równolegle z kalmoduliną i aneksynami. Ich znaczenie
podkreślają obserwacje świadczące, że ich poziom ulega zmianom w chorobach neurodegeneracyjnych, stanach zapalnych, miopatiach i w
różnych typach nowotworów. Białka S100A są również postrzegane jako wskaz
niki kliniczne różnych chorób, co jest nadal przedmiotem
intensywnych badań. W przedstawionym artykule omówiono również białka partnerskie białek z rodziny S100A.
436 www.postepybiochemii.pl