Postępy Biochemii 58 (4) 2012

429

Anna Cmoch

1,*

Patrick Groves

2

Małgorzata Palczewska

2

Sławomir Pikuła

1

1

Department of Biochemistry, Nencki Insti-

tute of Experimental Biology, Polish Acad-

emy of Sciences, 02-093 Warsaw, Poland

2

Department of Biological Chemistry, Instituto

de Tecnologia Quimica e Biologica, Universi-

dade Nova de Lisboa, Av. da Republica, 2780-

157 Oeiras, Portugal

*

Department of Biochemistry, Nencki Institute

of Experimental Biology, Polish Academy of

Sciences, 3 Pasteura Street, 02-093 Warsaw,

Poland; e-mail: [e-mail]

Received: October 10, 2012

Accepted: October 29, 2012

Key words: S100, annexins, signal transduc-

tion, calcium ions, calcium binding proteins

Abbreviations: AnxA — vertebrate annexin;

[Ca

2+

] — Ca

2+

concentration; CaBPs — calcium

binding proteins; ER — endoplasmic reticulum

Acknowledgements: This work was sup-

ported by a grant N N401 140639 from the Pol-

ish Ministry of Science and Higher Education

and by Polish-Portugal Executive Program for

years 2011-2012 (project 760) sponsored by the

Polish Ministry of Science and Higher Educa-

tion and by Portuguese Fundação para a Ciên-

cia e a Tecnologia.

S100A proteins in propagation of a calcium signal in norm and pathology

ABSTRACT

C

alcium ions are essential factors controlling the balance between cell survival, growth,

differentiation and metabolism. Ca

2+

acts as a global second messenger involved in the

regulation of all aspects of cell function. Fluctuations in the intra- and extracellular Ca

2+

con-

centration [Ca

2+

] in response to different environmental stimuli drive most cellular func-

tions. Therefore, sustenance of calcium homeostasis requires perfect organization in time

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

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

calcium signalling and homeostasis. The S100A subfamily is among the most distinctive of

EF-hand CaBPs and are found exclusively in vertebrates. They are believed to have evolved

to enable activation of specific biochemical pathways in parallel to the activity of Ca

2+

sen-

sors such as calmodulin and/or annexins. The importance of S100 proteins is underscored by

their deregulated expression in neurodegenerative and inflammatory disorders, myopathies

and cancer. In addition, S100 proteins serve as diagnostic markers in the clinic and are under

constant investigation. Their roles and the roles of the S100A protein partners in normal and

pathology will be also discussed.

InTroduCTIon

The role of Ca

2+

as a key and pivotal second messenger in cells depends largely

on a wide number of heterogeneous calcium binding proteins. The S100 family

of proteins comprises 25, homologous, acidic calcium binding proteins with the

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-

le the N-terminal EF-hand is non-canonical. The N-terminal EF-hand exhibits a

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-

led ‘S100-specific’ or ‘pseudo EF-hand’. S100 proteins are characterized by low

molecular weights (9–13 kDa as monomers). They possess broadly known abi-

lity to form oligomers (homodimers, heterodimers and oligomeric assemblies)

and are characterized by tissue and cell-specific expression [1-4]. There is a great

diversification of the identified S100 proteins, but solely they are present only in

vertebrates. S100 genes were not found in such model organism as Arabidopsis

thaliana, Drosophila melanogaster, Caenorhabditis elegans or Saccharomyces cerevisiae.

In evolutionary terms, the lowest organism reported thus far containing a pseu-

do EF- hand protein closely related to S100A is a chondrichthye (dogfish Squalus

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 ⁄A9, S100A4 and a Zn

2+

-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 Ca

2+

binding, although Zn

2+

and Cu

2+

have also been shown to regulate their biological activity. Binding of

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Ca

2+

to S100s exposes hydrophobic sites, which enable them

to interact with specific target proteins or membranes. Bin-

ding of the target protein in the presence of calcium often

results in an increase in calcium affinity of the S100 prote-

in as well [6-8]. Most S100 proteins are directly involved in

intracellular calcium signal transduction, Ca buffering and

in Ca uptake and transport. At low cytosolic [Ca

2+

], as in

the resting state of the cell, S100 proteins possess a closed,

relatively hydrophilic conformation. During cell activation

the cytosolic [Ca

2+

] increases due to Ca

2+

influx via plasma

membrane Ca

2+

channels and exchangers or due to their

release from intracellular Ca

2+

stores such as endoplasmic

reticulum (ER) and mitochondria. S100 proteins are charac-

terized by affinites for Ca

2+

, e.g. in a range that allows them

to respond to changes of cytosolic [Ca

2+

] (with one exception

of S100A10, which is Ca

2+

insensitive) [9-11]. The resulting,

Ca

2+

-dependent structural changes largely affect helix III

[12,13].

Intracellularly, S100 proteins act as Ca

2+

sensors, transla-

ting increases of cytosolic Ca

2+

level into a cellular respon-

se. S100 proteins display a relatively large range of calcium

binding affinity (K

D

20–500 µM). The binding of S100 pro-

teins to their targets is typically calcium-dependent, but

calcium-independent interactions have also been described

(S100A10-AnxA2). Evidence exists that Ca

2+

binding dicta-

tes the membrane binding affinity of S100A. Interestingly,

in some cases the interaction with membranes is weaker for

Ca

2+

bound S100A13 than in apo-S100A13 [14].

S100A2, S100A3, S100A6, S100A7, S100A8⁄9 and S100A12

bind Zn

2+

in specific structural sites. The binding of diffe-

rent metal ions results in conformational adjustments and

modulation of S100 protein folding and function in cells.

In the case of S100A12, Zn

2+

binding leads to an increase in

Ca

2+

affinity, whereas in S100A2 the opposite

effect was observed. On the other hand, Zn

2+

and Ca

2+

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 Cu

2+

at the same

sites to which Zn

2+

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 Ca

2+

-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].

S100 proteins are known to interact with

members of the other large family of cal-

cium binding proteins - annexins -(AnxA2

with S100A4, S100A6, S100A10 or S100A11

and AnxA6 with S100B, S100A6, S100A11,

S100A1) to form complexes that exhibit biological activities

[16-18] (Fig. 1).

S100A10 interacts not only with AnxA2 but also with

multiple proteins: serotonin receptor 5-HT1B, NaV1.8 so-

dium channel, TASK-1 potassium channel, ASIC-1 chan-

nels; TRPV5/TRPV6 channels, cytosolic phospholipase A

2

,

BAD (Bcl2-antagonist of cell death), AHNAK (neuroblast

differentiation-associated protein), cathepsin B, plasmi-

nogen activator, transglutaminase, S100A7, S100A8 [19].

Many functional consequences of the interactions between

S100A10 and its partners have been reported. There is accu-

mulating evidence that S100A10 interacts with a diverse set

of target proteins and regulates various biological functions

in different cellular compartments.

Most researchers concentrate on S100A10-annexin A2

heterotetramer formation and functions inside and outside

of the cell. Typically, S100A10 is found in most cells bound

to its annexin A2 ligand as the heterotetrameric S100A-

10

2

AnxA2

2

complex, AIIt. In addition to an intracellular di-

stribution, S100A10 is present on the extracellular surface

of many cells. It was indicated that it facilitates the translo-

cation of TRPV5 and TRPV6 channels towards the plasma

membrane in endothelial cells [20]. TRP (transient recep-

tor potential) channels constitute a superfamily of sensory

channels whose functions range from phototransduction

(where they were first described), olfaction, heat, cold sen-

sation etc., to Ca

2+

sensors/transporters. The TRP Ca

2+

chan-

nels are important for absorption of Ca

2+

into kidney, bone,

placenta, or intestine to maintain systemic Ca

2+

homeostasis.

The S100A10-annexin 2 complex specifically associates with

the C-terminal of TRP channels and is suggested to play a

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:

black is co-expression, dark blue is co-occurrence, purple is experimental evidence, light green is text

mining.

Postępy Biochemii 58 (4) 2012

431

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-

face. Active plasmin both degrades fibrin directly and ac-

tivates members of the matrix metalloproteases family,

creating a localized proteolytic hub during angiogenesis or

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

mechanism by which annexin A2 regulates the extracellular

levels of S100A10 is unknown.

Some ion channels that are regulated by calmodulin

may in fact be modulated by S100 proteins, either under

resting conditions or under special circumstances. Whether

the effect of S100 proteins is direct or indirect, knowledge

of the molecular basis for calmodulin interactions with ion

channels may be helpful in discerning how S100 proteins

modulate ion channels, in particular since there may well

be a similarity in their mode of action [25]. Some K

+

, Na

+

,

and Cl

−

channels are activated or modulated by intracellular

Ca

2+

signals giving rise to the notion that Ca

2+

binding pro-

teins may play a role in regulating channel gating function.

There is growing evidence for modulatory roles played by

the S100 proteins in the regulation of those types of chan-

nels. External binding of S100 proteins to ion channels has,

however, not been reported so far [26].

S100A4, the recently recognized novel binding partner of

AnxA2, manages various functions dependent on cellular

compartmentalization. Intracellular S100A4 exists as a sym-

metric homodimer that facilitates the binding of its target

proteins (actin, nonmuscle myosin IIA and IIB, tropomy-

osin). Extracellular S100A4 interacts with AnxA2, MMP-13,

RAGE or epidermal growth factor (EGF) receptor ligands.

Through these interactions, S100A4 regulates cell mobility,

invasion, and angiogenesis [27,28]. S100A4 was reported

as involved in the regulation of osteoblastic transcription

factors Runx2/Cbfa1 and Osx. S100A4 plays an important

role in matrix remodeling by up-regulating the expression

of crucial matrix metalloproteinases (MMPs) of bones [29].

S100A1 is known to increase the L-type Ca

2+

channel (L-

-type Ca

2+

channels located in the SR) current at nanomolar

Ca

2+

concentrations and enhances Ca

2+

release in skeletal

and in cardiac muscle. S100A1 was shown to directly in-

teract with PKA and this complex appears to affect Ca

2+

channels. At the molecular level, S100A1 was shown to

interact in a Ca

2+

-dependent manner with the cardiac iso-

forms of RYR2 (ryanodine receptor, isoform 2) (Fig. 2) [30],

SERCA2A (sarco/endoplasmic reticulum calcium ATPase,

isoform 2A) [31], phospholamban (PLN), titin, and the mi-

tochondrial F1-ATP synthase in complex V of the respira-

tory chain [5].

S100A proteins have been also intensively studied for

their interaction with heat shock-regulated proteins. For

example, S100A6 mediates nuclear translocation of Sgt1

and its interaction with Hsp-90 [32,33]. S100A1 and S100A2

proteins regulate the Hsp-90 interaction with target proteins

[34]. S100A1 is also known to be a component of the Hsp70/

Hsp90 multichaperone complex [35].

CELLuLAr FunCTIonS oF S100A ProTEInS

A richness of possible targets for S100 proteins is in

accordance with their multiple functions. Therefore, S100

proteins regulate a diverse array of cellular activities,

including the differentiation [36] and apoptosis [37,38],

motility, membrane–cytoskeleton interactions and cyto-

skeleton dynamics [39,40], cellular Ca

2+

homeostasis [41],

transduction of intracellular Ca

2+

signals, innate and ada-

ptive immunity [1,2,25,42] and are predicted to partici-

pate in mineralization [43]. Up to now, only S100A4 and

S100A8/A9 have been considered as factors involved in

mineralization control [44-46]. They have been also re-

ported as cellular protectors from oxidative cell damage,

regulators of protein phosphorylation [47], secretion and

transcriptional factors [1-3]. S100A8/A9 complex, was re-

ported as a Ca

2+

sensor which controls the interplay be-

Figure 2. Molecular mechanisms of S100 target protein interactions. In the presen-

ce of elevated Ca

2+

concentrations, apo-S100 undergoes a conformational change

and interacts with target proteins in a Ca

2+

-dependent pathway. The interaction

of S100A1 and RyR receptors is shown as a specific example. In contrast, S100A10

interacts with annexin A2 independently of Ca

2+

.

432

www.postepybiochemii.pl

and vascular smooth muscle cells, neurons, astrocytes,

Schwann cells, epithelial cells, myoblasts and cardiomy-

ocytes [49]. Multimeric assemblies seem to be necessary for

the extracellular functions of S100 proteins and have been

reported for S100A12, S100A4, S100B and S100A8/A9 [3].

S100-associated cell signalling may be promiscuous. This

can be best exemplified through S100A8 ⁄A9, which pro-

motes RAGE-dependent cell survival as well as multiple

RAGE-independent cell death pathways.

This diversity in function of the S100 provides evidence

of very extensive evolutionary optimization of the fit be-

tween the EF-hand CaBPs fold and the calcium ion. S100

proteins form a phylogenetically young group among the

EF-hand proteins (present only in verterbrates). Future rese-

arch in the coming years will certainly contribute to clarify

some of these and other questions and will ultimately bring

us to a higher level of understanding the biology of tumour

and degeneration and enable to use our acquired knowled-

ge of S100 structure and functions in developing strategies

to modulate their activity for therapeutic purposes [51].

rEGuLATIon oF S100A FunCTIonS BY

PoSTTrAnSLATIonAL ModIFICATIonS

A number of posttranslational protein modifications have

been described. Posttranslational protein modifications may

result in physiochemical changes of the protein with respect

to mass, charge, structure and conformation. S100 proteins

may be modified by various post-translational modifica-

tions, including phosphorylation, methylation, acetylation,

and oxidation. These modifications may alter their ion-bin-

ding properties, interactions with target proteins, transloca-

tion within cell compartments, degradation, protein-protein

interactions and extracellular functions.

tween extracellular Ca

2+

entry and intraphagosomal ROS

production [48].

Within the cells, S100 proteins often translocate from

one compartment to another (nucleus, cytoplasm) in re-

sponse to changes in calcium concentration or concentra-

tion of extracellular S100 using different translocation pa-

thways. In addition to their intracellular functions, S100

proteins can also be secreted and may exert the role of

cytokines (e.g. S100A4, S100A8, S100A9) through the ac-

tivation of various cell surface receptors in an autocrine

and paracrine manner through various receptors RAGE

(Fig. 3), toll-like receptor 4 (TLR-4) (Fig. 4), G-protein-co-

upled receptors, scavenger receptors or heparan sulfate

proteoglycans and N-glycans

[25]. S100B, S100P, S100A4,

S100A6, S100A8/A9, S100A11 and S100A12 are known to

interact with RAGE [49], while S100A8/A9 also bind Toll-

-like receptors or TLRs [50]. Some S100 proteins, including

S100A4, S100A7, S100A8 ⁄A9, S100A11, S100A12, S100B

and others, are commonly secreted, exhibiting cytokine-

-like and chemotactic activity. When S100A7, S100A8,

S100A9, S100A12 or S100B are secreted in response to cell

damage or activation, they act as alarmins (cellular stress

signals), activating other immune and endothelial cells.

Frequently, S100 poroteins are secreted upon Ca

2+

signa-

ling via vesicle fusion with the cell membrane into the

extra cellular space, where they might acquire oligomeric

structures specialized for extracellular functions [5].

S100 proteins can also be released into the extracellular

space in response to stimuli, or during cell damage, and

they promote responses including neuronal survival and

extension (S100B), apoptosis (S100A4 and S100A6), inflam-

mation (S100B, S100A8/A9, S100A11 and S100A12), au-

toimmunity (S100A8/A9), chemotaxis (S100A8/A9) and

cell proliferation and survival (S100P, S100A7), effectively

functioning as paracrine and autocrine mediators. Thus,

extracellular S100 proteins exert regulatory activities on

monocytes/macrophages/microglia, neutrophils, lym-

phocytes, mast cells, articular chondrocytes, endothelial

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.

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

with scavenger receptor. From LeClerc et al. [4], modified

Postępy Biochemii 58 (4) 2012

433

S100 proteins can be modified post-translationally by

phosphorylation (S100A8/A9, S100A11), nitrosylation

(S100A1, S100B, S100A8), citrullination (S100A3) (34), car-

boxymethylation (S100A8/A9), glutathionylation, trans-

amidation (S100A11) or sumoylation. These modifications

often modulate the interaction with calcium or target pro-

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).

Extracellular functions of several S100s may be regula-

ted by oxidative modifications. Many redox-based signa-

ling pathways are regulated by reversible modifications

such as intra- and interprotein disulfides, S-nitrosylation

and glutathionylation. Cysteine S-nitrosylation is a new fac-

tor responsible for increasing functional diversity of S100A

proteins and helps explain the role of S100A as a Ca

2+

si-

gnal transmitter sensitive to NOS/redox state within cells.

S100A1 has been recently reported in PC12 cells to be endo-

genously S-nitrosylated at site important for target binding

[52]. S100A8 and S100A9 are S-nitrosylated by NO donors

including GSNO, the physiological regulator of NO trans-

port and signaling. S100A8 is preferentially nitrosylated in

the S100A8/A9 complex. S-nitrosylation of S100A9 is cal-

cium-dependent, whereas S100A8 is not. In contrast to the

proposed, protective role of extracellular S100A8 and to

some extent, S100A9, these proteins regulate intracellular

NADPH oxidase activity and thus, ROS (reactive oxygen

species) generation. Thus, there is a paradigm on dual roles

of S100A8/A9 in redox balance. Oxidation may represent a

switch, whereby the modified proteins display their func-

tions [53].

Phosphorylation of Ser and Thr residues increased the af-

finity of S100A for the p53 TAD domains. Conversely, acety-

lation and phosphorylation of the C-terminus of p53 decre-

ased the affinity for S100A2 [15]. S100A9 protein has been

also reported as phosphorylation target for MAPK [54].

Phosphorylation of that protein leads to S100A8/A9 hete-

rotetramer translocation and NOX2 activation. Kouno et al.

[55] proposed phosphorylated S100A11 to be recognized by

its target protein, nucleolin and in such complex transloca-

ted to the nucleus.

Sumoylation of two lysines in S100A4 molecule results in

nuclear translocation of this protein and its action as trans-

cription factor bound to the promoter region of MMP-13

[29,53]. Up to date S100 proteins have not been described to

be glycosylated.

dErEGuLATIon oF S100A GEnES EXPrESSIon

Deregulated expression of genes encoding members of

the S100 family of calcium-binding proteins has been asso-

ciated with multiple tumor types. S100A2, S100A4, S100A6

and S100A10 genes alterations have been associated with

brain tumors. Furthmore, the methylation/demethylation

of these genes plays a role in the control of their tumor gene-

rating potency [56]. S100A1 is thought to modulate the Ca

2+

sensitivity of the sarcoplasmic reticulum (SR) Ca

2+

release

channels (ryanodine receptors or RyRs) and chronic absence

of S100A1 results in enhanced L-type Ca

2+

channel activity

combined with a blunted SR Ca

2+

release amplification in

cardiomyocytes [57]. The loss of S100A10 from the extracel-

lular surface of cancer cells results in a significant loss in

plasmin generation. In addition, S100A10 knock-down cells

demonstrate a dramatic loss in extracellular matrix degra-

dation and invasiveness as well as reduced metastasis [58].

The specific knockdown of S100A4 strongly suppressed cell

growth, migration and invasion activities in cancer cells,

therefore S100A4 may positively regulate tumor cell proli-

feration, invasion and metastasis associated with multiple

molecules [59].

S100A ProTEInS In HuMAn dISEASES

— CLInICAL SIGnIFICAnCE

Members of the S100 protein family have been shown to

posess pathophysiologic implications. In addition, members

of the S100 protein family are extensively tested as useful

biomarkers of certain diseases and potential targets of clini-

cal therapies [60]. There is growing evidence that expression

of S100 proteins is altered in pathologies. The S100 protein

levels are associated with a wide array of pathological con-

ditions like chronic inflammation [1,2,61-65], immunode-

fence [27], cardiomyopathies [30,66-68], atherosclerosis [69],

rheumatoid arthritis [70,71], cystic fibrosis [72] and cancer

Figure 5. Intracellular and extracellular roles of S100A proteins. Shown are the best known targets/activities putatively regulated by S100A proteins in a Ca

2+

-dependent

and Ca

2+

-independent manner. From Donato et al. [1], modified.

434

www.postepybiochemii.pl

[1,2,61,73-89]. S100 proteins are thought to be also associa-

ted with diabetes and its complications [80], neurodege-

neration and Alzheimer disease [90,91] and posttraumatic

stress disorder [92].One of the most intringuing directions

in research on S100A proteins is their involvement in neuro-

nal plasticity regulation and depression [19].

Functions of some S100A proteins in cancer progression

are opposite to others, for example down-regulation of

S100A6 and S100A10 in breast cancer, irrespective of patho-

logical stage, was observed whereas S100A7, S100A8 and

S100A9 were strongly up-regulated only in some type of

breast cancer [93]. There are many factors that can modu-

late S100A expression in biological systems. For example,

the S100A10 coding gene is regulated by various factors:

dexamethasone, TGF-α, EGF, NO donors, interferon-γ, vita-

min D, retinoic acid, NGF, electroconvulsive treatment [19].

Up regulation of S100A10 occurs also in response to AnxA2

upregulation. Down-regulation of AnxA2 is coordinated

with lack of S100A10 protein, but the specificity of mecha-

nism which is responsible for that phenomenon still rema-

ins unknown. Here we provided the examples of complica-

ted regulation of S100A proteins functions and expression.

ConCLudInG rEMArKS And FuTurE PErSPECTIVES

The thesis is emerging that S100 proteins are phyloge-

netically new proteins displaying the unusual property of

acting both within cells as Ca

2+

sensor proteins implicated

in Ca

2 +

signal transduction, and outside cells as ligands for

specific cell surface receptors on an increasingly larger num-

ber of cell types. Therefore the grand challenge ahead is de-

termining the role of particular S100A proteins in diseases

related to Ca

2+

homeostasis disorder such as neurological

diseases and artheriosclerosis.

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436

www.postepybiochemii.pl

udział białek S100A w przekazywaniu sygnału

wapniowego w normie i patologii

Anna Cmoch

1,*

, Patrick Groves

2

, Małgorzata Palczewska

2

, Sławomir Pikuła

1

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 odgrywają rolę przekaźnika 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 odpowiedź 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 wskaźniki kliniczne różnych chorób, co jest nadal przedmiotem

intensywnych badań. W przedstawionym artykule omówiono również białka partnerskie białek z rodziny S100A.

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