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J. Biol. Chem., Vol. 275, Issue 32, 24233-24236, August 11, 2000
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andFrom the Department of Cell Biology and Cell Adhesion and Matrix Research Center, University of Alabama at Birmingham, Birmingham, Alabama 35294
Integrins are a major family of cell-matrix and
cell-cell receptors. Bidirectional signal transmission between the
extracellular matrix or other integrin ligands and the submembranous
cytoskeleton and associated adaptor proteins is now being resolved
(1-6). This review will concentrate on an emerging area of study: how the type of adhesion and the signaling following integrin ligation may
be modulated by lateral interactions with other membrane components. This may occur through direct or indirect interactions. Two major groups of transmembrane proteins will form the focus of this review. One group, the tetraspans or TM4SF proteins (7-9), is composed of
transmembrane proteins implicated in regulation of cell migration and
invasion. They can interact directly with the extracellular domain of
the Because of space constraints, integrin interactions with other
transmembrane proteins will only be briefly mentioned. The first
integrin-associated transmembrane protein
(IAP,1 CD47) was cloned in
1993 (16). This is a receptor for the cell-binding domain of
thrombospondin (17), and it can regulate vitronectin binding to
Tetraspans/TM4SFs are a large family of transmembrane proteins,
which have four transmembrane domains, short N- and C-terminal cytoplasmic tails, and two extracellular loops (reviewed in Refs. 7-9). The transmembrane domains are the most highly conserved between
family members, particularly the inclusion of polar amino acids, and
the sequences of hydrophobic residues. There are also 2-3 conserved
charged residues in the 4-amino acid cytoplasmic loop between
transmembrane domains 2 and 3, including a glutamic acid residue.
These, together with a PXSC motif and the conserved placement of 3 cysteines in the large extracellular domain form the
structural basis for the family classification (7-9). The extracellular domains of tetraspans/TM4SFs are otherwise divergent between each family member and, except for some conservation of glycosylation sites, are Tetraspans/TM4SFs are very widely expressed and can interact with
themselves, other tetraspans/TM4SFs, and a range of other cell surface
components. Because of the multicomponent complexes they participate
in, they have been termed "adaptor" or "facilitator" molecules
(7, 8). Some are nearly ubiquitously expressed (e.g. CD9,
CD63, and CD81), whereas others are limited to platelets, immune cells,
or neuronal cells (reviewed in Refs. 7-9). Many were originally
identified as tumor-associated proteins and implicated in changes in
adhesion, motility, metastatic potential, or proliferation (7-9). For
example, CD9 transfection into carcinoma cells reduced motility and
metastasis, and reduced CD9 expression accompanies poor prognosis in
breast carcinoma (29). They also may play role(s) in development. For
example, the Drosophila lbl gene is needed for
normal formation of neuromuscular junctions, CD9 is transiently
expressed during neuronal development, and the complement of
tetraspans/TM4SFs expressed by T and B cells differs with the developmental stage (reviewed in Refs. 7-9).
Recently (30) tetraspans/TM4SFs were found to interact with
integrins. The association is constitutive, e.g. in resting platelets (31), and independent of adhesion because it occurs in cells
in suspension (32). Most studies have used co-immunoprecipitation under
low stringency conditions and surface cross-linking and have identified
integrin-tetraspan/TM4SF interactions with
Integrins and tetraspans/TM4SFs co-localize in clusters, particularly
at leading lamellae of cells or in "footprints" left after cell
detachment (28, 30-32, 34) or at intercellular contact sites (35).
However, tetraspans/TM4SFs seem to be excluded from focal adhesions
(28, 30-32, 34, 36). Indeed, in CHO co-transfection experiments, CD9
colocalized with Tetraspan/TM4SF interaction with integrins may provide indirect
association of integrins, which do not have intrinsic enzymatic activity, with enzymes or other signaling molecules. Src family tyrosine kinase and lesser amounts of serine/threonine kinase activities associate with CD63- Cell surface proteoglycans can modify cell adhesion and migration,
similar to the tetraspans/TM4SFs (reviewed in Refs. 10-15). Several
early studies indicated a need for interaction of both heparin binding
and "cell" binding motifs for the development of stress fibers and
focal adhesions in a variety of anchorage-dependent cells
(reviewed in Ref. 14). This has been confirmed recently (42, 43). Cell
attachment and spreading appears to be integrin-mediated, whereas later
cytoskeletal organization appears to be heparan sulfate
proteoglycan-mediated (14), with concomitant activation of PKC (44). A
study monitoring CHO responses through transfected There is one report of a syndecan being coimmunoprecipitated with
CD9 tetraspanin/TM4SF, which also associates with integrin
INTRODUCTION
chain of specific integrins. The second group, the syndecans
(10-15), has not been shown to bind integrins directly but to bind to
separate domains within integrin ligands. These also modify
integrin-based adhesion, migration, invasiveness, and matrix assembly.
The similarities in integrin modulation will be discussed.
Integrin-binding Transmembrane Proteins
v
3 (16, 18) and activate
IIb3 through thrombospondin binding (19).
Mice lacking IAP have decreased resistance to bacterial infection
probably because of delayed neutrophil migration to the site of
infection and defective activation (20). IAP may also interact with
21 integrin in vascular smooth muscle cells (21). Second, integrin and growth factor signaling pathways intersect, and a subset of highly phosphorylated platelet-derived growth factor and insulin receptors, together with other
downstream signaling components, coprecipitates with
v3 after treatment of cells with
platelet-derived growth factor or insulin (22). Third, urokinase
plasminogen activator receptor (CD87) co-immunoprecipitates with
1, 2, and 3 integrins
(23). Other membrane molecules (reviewed in Ref. 9) shown to interact
by co-immunoprecipitation are CD98 (with
31), which may regulate 1
integrin activation (24), CD36 (with
IIb3), and CD46 (with
31). It is not yet clear whether
interactions seen by co-immunoprecipitation are direct or due to
formation of membrane microdomains containing multiple components, but
some cross-linking studies (reviewed in Refs. 7-10) indicate direct
binding. In addition, EMMPRIN/basigin (CD147), which regulates matrix
metalloproteinase production, co-immunoprecipitates and colocalizes
with 31 and
61 integrins (25) and can be cross-linked
to these at the cell surface. The dystrophin complex can also associate
with 1 integrins, possibly through and 
sarcoglycan (26). Finally, several studies (Ref. 27 and references
therein) demonstrate that 41, but not
51, integrin-mediated melanoma cell
adhesion requires a transmembrane chondroitin sulfate proteoglycan
(MCSP in human, NG2 in rat). A sequence in the 4
integrin subunit can bind directly to chondroitin sulfate
glycosaminoglycan and, when used as an antagonist, can block
41-mediated melanoma cell adhesion
(27).
Tetraspan/TM4SF Proteins
80% identical between species. An
exception to this is the tetraspan/TM4SF (NAG-2), which is 90%
conserved between mouse and human (27).
Tetraspan/TM4SF Interactions with Integrins
41, 31,
61, and
IIb3 with cell type-specific or
contradictory reports for 21,
51, or L2
(reviewed in Refs. 7-9). Although deletion/chimeric transfection
studies indicate tetraspans/TM4SFs interact through the extracellular
domain of the subunit (32, 33), hydrophobic interactions may play
some role (31), and the subunit may also contribute because,
although 61 does interact,
64 does not (30, 34).
IIb3 integrin only in
clusters at the leading edge of lamellae, whereas
IIb3 was additionally present in focal
adhesions in cells seeded on fibrinogen (31). Furthermore, CD9
transfection of CHO cells did not alter focal adhesion formation (31).
However, transfection with CD9 did alter actin cytoskeleton
organization in HT1080 cells (36), and the effect varied with
substrate. Most studies point to a role for tetraspans/TM4SFs and their
associated integrins (e.g. 31
and 61) in migration rather than adhesion
per se (8, 35, 37). This is highlighted by one study (33)
that confirmed a stable, specific interaction of one tetraspan/TM4SF
(CD151) with integrin 31 by
co-immunoprecipitation under stringent conditions. Unlike previous
studies, where only subsets of tetraspan/TM4SF or integrin molecules
interacted, most (70-90%) of 31
associated with CD151 and no additional cell surface components were
co-immunoprecipitated. Antibodies against either CD151 or
31 dramatically reduced neutrophil migration, confirmed in a separate study (35).
Anti-31 (but not
anti-61) or anti-CD151 (but not anti-CD9)
specifically inhibited neurite outgrowth, with no effect on adhesion.
It remains to be seen whether the association of
31 with CD151 is responsible for the
previously observed association of 31
with CD9, CD63, CD81, and NAG-2 (33).
Tetraspan/TM4SF Signaling
2 integrin complexes
(37), and CD53 binds an unknown tyrosine phosphatase (38). Conventional protein kinase C (cPKC) isotypes can associate with CD81 and CD151 (9)
after activation. Phosphatidylinositol 4-kinase (PI4-K; probably type
II) associates constitutively with a multicomponent complex containing
the tetraspans/TM4SFs CD63, CD81, and 31 (32) and with the CD151-31 complex (33).
Indeed, 95% of PI4-K activity was associated with
31 through CD151 with only minor amounts
through CD63 and CD81. The enzyme associates with the tetraspan/TM4SF
protein rather than 31 (32, 33).
Interestingly, clustering the
31-CD63-CD81 complex with antibodies to
either tetraspan/TM4SF protein did not induce tyrosine phosphorylation of FAK or pp130cas, whereas clustering with anti-integrin did.
HT1080 cells containing CD9 do, however, differ in FAK phosphorylation
from wild type, and again this depends on which substrate is used for
adhesion (36). Furthermore, antibodies against CD63, CD82, or CD151 all potentiated FAK phosphorylation when present as a mixed substrate with
collagen (36), but adhesion to these antibodies alone reduced the level
of FAK phosphorylation below even that seen in suspended cells. Thus,
signaling through the tetraspans/TM4SF proteins appears complex. This
recent study also demonstrated that tetraspan/TM4SF proteins are only
weakly associated with the actin cytoskeleton (36). Thus, interactions
of tetraspan/TM4SF proteins with their ligands has been suggested as an
alternate signaling pathway leading to weak or transient
cell-matrix-cytoskeleton interactions suitable for lamellipodial
extension and retraction. CD9, CD63, CD81, CD82, and CD151 colocalize
at punctate structures at the cell periphery, rather than focal
adhesions, and although some colocalization of talin and FAK occurs,
they do not appear to colocalize with vinculin- or paxillin-containing
structures (36). Integrins are inserted at the leading edge of cells
(reviewed in Ref. 39), PI4-K is implicated in vesicular transport (40),
and CD63 has an internalization motif (41), which allows for
lamellipodial colocalization of integrin/CD63 and rapid
re-internalization of 31 if complexes are
not stabilized.
Cell Surface Proteoglycans
IIb3 to fibrinogen substrates (45) showed
that antibody-coated substrates, whether integrin-activating or not,
induced only limited spreading; full spreading required additional
activation of PKC, and stress fiber formation followed Rho activation.
The roles of the G proteins Rac, Rho, and Cdc42 in cell spreading and
stress fiber/focal adhesion formation have been recently reviewed (46). Thus, there appear to be three sets of signaling involved in focal adhesion assembly: tyrosine phosphorylation events associated with
integrin ligation, PKC activation associated with cell surface proteoglycan interactions, and Rho-GTP signaling.
Syndecans in Cell Adhesion
1 (47). Direct interactions of syndecans with integrins
have not been reported, but co-immunoprecipitation under low stringency such as used for tetraspan/TM4SF-integrin interactions has not been
described. Syndecans have a single transmembrane domain, a short
cytoplasmic domain, and a larger extracellular domain that bears 3-5
glycosaminoglycan chains, mostly heparan sulfate (10-15). The four
mammalian syndecans have cell and developmental expression specificity
(48). Briefly, syndecan-1, -2, and -3 are the major syndecans of
epithelial, fibroblastic, and neuronal cells, respectively, whereas
syndecan-4 is unusual, appearing as a minor component of most cells.
Syndecan core proteins range in size from ~20 kDa (syndecan-4) to
~45 kDa (syndecan-1) as deduced from sequencing, which is not unlike
that of tetraspans/TM4SFs (Table I). Like
the tetraspans/TM4SFs, syndecan core proteins have high homology in the
transmembrane domain. In addition, however, syndecans have two
cytoplasmic regions, proximal and distal to the membrane, that are also
highly conserved. We have termed these C1 and C2, respectively (14). In
between these constant regions is a small cytoplasmic sequence (denoted
V) unique to each syndecan but conserved between species. This has led
to suggestions of syndecans having common and unique functions (14,
15). The extracellular domains are highly divergent except for the
glycosaminoglycan attachment sites (10-15), even for the same syndecan
of different species.
Similarities and properties of tetraspans and syndecans
Syndecans can bind a wide range of extracellular matrix molecules, growth factors, lipoproteins, and enzymes through their heparan sulfate chains (10-15). This has led to them being regarded as "co-receptors" for cell surface binding and internalization of a number of ligands (10). However, their precise roles in binding, presentation, and signaling are only now being revealed. Transfection experiments with syndecans have indicated that they can affect adhesion and/or migration. Syndecan-1 was the first to be cloned and has been the most studied. Expression of syndecan-1 in lymphocytes results in decreased invasion of collagen gels (49), whereas reduction of syndecan-1 in epithelial cells results in the cells appearing fibroblastic and invading collagen gels (50). This correlates with a loss of E-cadherin, and conversely, down-regulation of E-cadherin results in down-regulation of syndecan-1 (51). Syndecan-1, like tetraspans/TM4SFs, can be a prognosis marker for tumor progression (52). When expressed in Schwann cells, syndecan-1 led to increased cell spreading and stress fiber formation, and the transfected syndecan-1 codistributed with microfilaments during spreading but was not inserted into the focal adhesions that ultimately formed (reviewed in Ref. 12). Syndecan-1 and -3 can both codistribute with the microfilament system if clustered with antibodies against the ectodomain (12). Syndecan-2 overexpression also results in increased spreading (53) but does not increase focal adhesion formation nor is it a focal adhesion component in transfected cells or normal fibroblasts (54).
Syndecan-4, unlike integrin-associated tetraspans/TM4SFs, is localized
to focal adhesions on a variety of substrates (54, 55), codistributed
with 51 or
v3 integrins in fibroblasts on
fibronectin or vitronectin substrates, respectively (54). Its presence,
therefore, is not limited to one specific integrin, but association may
be limited to those integrins involved in focal adhesion formation.
Primary fibroblasts will attach and spread on substrates coated with
the "cell-binding" domain of fibronectin but do not form focal
adhesions or stress fibers (42, 43, 56). Addition of clustering
antibodies against syndecan-4 ectodomain can promote focal adhesion
formation in cells prespread on the cell-binding domain of fibronectin
(43).
Overexpression of syndecan-4 in CHO cells leads to an increase in
spreading, accompanied by increased formation of focal adhesions and
stress fibers (53). Expression of antisense cDNA for syndecan-4 or
of a core protein with a truncated cytoplasmic domain, in contrast, leads to a decrease in spreading, focal adhesion, and stress fiber formation (53), confirming that signaling through syndecan-4 (see
below) is fundamentally involved in cytoskeletal organization. Promotion of focal adhesion formation appears to be through clustering of the core protein, because this will occur if syndecan-4 core protein
is overexpressed in mutant CHO cells that cannot add heparan sulfate
chains and do not normally form focal adhesions (57). Syndecan core
proteins spontaneously oligomerize (reviewed in Ref. 12).
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Syndecan-based Signaling |
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Syndecan-4 cytoplasmic domain can bind PKC and its
constitutively active catalytic fragment PKM in vitro (58).
It also associates in vivo with PKC as shown by
co-clustering, co-immunoprecipitation, and affinity chromatography.
Furthermore, interactions require prior activation of PKC, presumably
to translocate PKC from the cytoplasm to the membrane (58). The site in
syndecan-4 that binds PKC is its unique cytoplasmic V region,
comprising the sequence LGKKPIYKK (58). The maximal activity of PKC
induced by phospholipid mediators, or of PKM, is enhanced in
vitro by interaction with syndecan-4 core protein or with
synthetic peptides encompassing the V region sequence (58). This
requires multimerization of the core protein (54), which is a property
of all syndecans (10-15). Phosphatidylinositol 4,5-bisphosphate
(PIP2) promotes the oligomerization of the cytoplasmic
domain of syndecan-4 (59, 60). PIP2 is itself an activator
of cPKC isoforms and does not need to be cleaved by phospholipase C to
diacylglycerol to achieve activation. Furthermore, syndecan-4
potentiates PKC activation by PIP2 and abrogates the
requirement for high levels of calcium needed for in vitro
activity of the cPKC isoforms (60). Recent NMR studies (61) have
indicated that the LGKKPIYKK (4V) peptide capable of activating
PKC forms parallel dimers, in "twisted clamp" structures (Fig.
1), to which PIP2 binds on one face,
potentially leaving the opposite face
available for interactions with PKC or other
syndecan-4/PIP2 oligomers. PIP2 also stabilizes
syndecan-4 cytoplasmic domain dimer formation (61) and in
chromatographic experiments promotes the formation of tetra- and
octamers (60).
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In addition to its effects on cell adhesion, syndecan-4 acts as a coreceptor in fibroblast growth factor signaling; its C1 domain is serine-phosphorylated in serum-starved endothelial cells (62). Dephosphorylation following fibroblast growth factor binding allows syndecan-4 core protein multimerization, revealing a mechanism for regulation of PKC binding and activation (63). Thus, syndecan-4 may play a pivotal role in the interplay between growth factor- and integrin-mediated signaling. Recent studies (43) have also indicated that syndecan-4 may activate Rho GTPase.
Syndecan-2 does not activate PKC but is itself a substrate for phosphorylation by PKC (Ref. 64 and references therein), which may be of importance in its effects on matrix synthesis (65). Syndecan-3 is preferentially expressed in the growth cones of neurites; interactions with its ligand HB-GAM promote growth cone extension, and its C1 region interacts with components of the Src-cortactin signaling pathway following interaction with its ligand (66). Interactions of the terminal EFYA sequence of the cytoplasmic domains of syndecans have been demonstrated with two PDZ proteins (syntenin (67) and CASK (68)), which may promote the formation of clusters of these proteoglycans. CASK contains a binding site for protein 4.1 (69). This may allow additional interactions between clustered membrane receptors and the cytoskeleton (reviewed in Ref. 15). CASK also has an SH3 domain capable of localizing adaptor/signaling molecules to multimeric complexes.
Syndecan regulation of adhesion may not be confined to cytoplasmic
domain signaling. Expression of a tail-less syndecan-1 reduces matrix
invasion by lymphocytes (49), and the cytoplasmic domain is not needed
for retention in detergent-resistant cytoskeletal preparations
(reviewed in Ref. 12). This, again, suggests some lateral association
with other membrane molecules that are themselves somehow linked to the
cytoskeleton. Further, recent data suggest a site in the ectodomain of
syndecan-4 can interact with an unidentified surface molecule to
promote adhesion without the need for the cytoplasmic domain (70). This
is an important area for investigation with potential parallels to
tetraspan/TM4SF biology.
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Common Features of Integrin Response Modifiers |
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Despite different structural characteristics, tetraspans/TM4SFs
and syndecans have some strikingly convergent properties, some of which
are listed in Table I and shown schematically in Fig.
2). They have similar protein sizes, very
small cytoplasmic domains, and larger, but poorly conserved,
ectodomains. Possibly structural motifs are conserved, whereas their
constituent primary sequences are not. Perhaps most remarkable is the
property of CD81, CD151, and syndecan-4 to bind activated cPKC
(reviewed in Refs. 9 and 14). Direct interactions of PKC isoforms with transmembrane molecules are rare. PKC binding to tetraspans/TM4SFs may
lead to serine phosphorylation of integrin 3 and
6 subunits (9), and the role of PKC in cytoskeletal
organization is now emerging as a major field of study (e.g.
Ref. 4 and references therein). Syndecan-4 may localize PKC to
forming focal adhesions, promote stable adhesion, and thereby reduce
cell migration. Conversely, the same PKC bound to tetraspans/TM4SFs may
enhance cell migration, because tetraspans/TM4SFs appear to be
uniformly excluded from focal adhesions. How this system is balanced in
cells is intriguing and may explain why PKC activation in different
cell types can either promote adhesion or migration (4).
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Another common connection is with phosphoinositide metabolism.
Syndecan-4 cytoplasmic domain dimers are stabilized by interactions with PIP2 (60, 61). Synthesis of this phospholipid is
enhanced by integrin ligation and Rho and Rac activation (reviewed in
Ref. 46). Many actin-associated protein functions are regulated by PIP2 (e.g. gelsolin, profilin, vinculin, ERM
proteins) and, indeed, the assembly of focal adhesions may depend on
its presence (71). With syndecan-4/PIP2 interactions, this
may lead to a ternary signaling complex with PKC activity being
potentiated by concurrent interactions of its catalytic domain with the
proteoglycan V region and its regulatory domain with PIP2.
The functional consequence of PI4-K binding to some tetraspans/TM4SFs
has also not been resolved. Clearly, it may also regulate inositol
phosphate metabolism to regulate cytoskeletal interactions.
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Conclusions |
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The emerging paradigm is that lateral interactions of the
tetraspans/TM4SFs, syndecans, and perhaps other transmembrane molecules act as response modifiers for integrin function. Integrins do not have
intrinsic kinase activity, and that activity may be the "collaborator" function to control signaling. Integrins associate with tyrosine kinases, e.g. FAK, pp130cas,
Src, and integrin-linked kinase intracellularly, with effects on
focal adhesion disassembly, growth, apoptosis, and matrix assembly.
Tetraspans/TM4SFs and syndecans may optionally contribute finetuning of
cytoskeletal organization through regulation of phosphoinositide
metabolism and PKC location and activity.
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ACKNOWLEDGEMENTS |
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We thank colleagues for interesting discussions and apologize for the use of reviews rather than primary papers because of space constraints. We thank Dr. Weontae Lee and Donghan Lee (Yonsei University, Seoul, Korea) for Fig. 1.
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FOOTNOTES |
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* This minireview will be reprinted in the 2000 Minireview Compendium, which will be available in December, 2000. This is the fourth article of four in the "Integrins Minireview Series." This work was supported in part by National Institutes of Health Grants GM50194 (to J. R. C.) and DK54605 (to A. W.) and a subproject of National Institutes of Health Grant AR20614 (to A. W.). Partial support to the authors was from the Sankyo Chemical Company.
To whom correspondence should be addressed: Volker Hall 203A,
Dept. of Cell Biology, University of Alabama at Birmingham, Birmingham,
AL 35294-0019. Tel.: 205-934-1548; Fax: 205-975-9956; E-mail:
awoods@cellbio.bhs.uab.edu.
Published, JBC Papers in Press, May 4, 2000, DOI 10.1074/jbc.R000001200
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ABBREVIATIONS |
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The abbreviations used are: IAP, integrin-associated transmembrane protein; CHO, Chinese hamster ovary; cPKC, conventional protein kinase C; PI4-K, phosphatidylinositol 4-kinase; FAK, focal adhesion kinase; PKC, protein kinase C; PIP2, phosphatidylinositol 4,5-bisphosphate.
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INTRODUCTION
Integrin-binding Transmembrane...
