Regulation of fibronectin receptor distribution [published erratum appears in J Cell Biol 1992 Jul;118(2):491]

LaFlamme, Susan E.; Akiyama, S K; Yamada, Katsushi

doi:10.1083/jcb.117.2.437

Cited by 266 publications

(62 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Early studies on integrin-dependent cell adhesion and signalling demonstrated that cell ligation to the ECM was accompanied by integrin aggregation, and that this clustering could trigger increased tyrosine phosphorylation of a number of intracellular proteins [22][23][24][25]. Additional work demonstrated that integrin clusters are concentrated in specialized organelles known as focal adhesions, which are also enriched with bundles of actin and associated cytoskeletal proteins, including vinculin, talin, paxillin and tensin [17,26].…”

Section: Fakmentioning

confidence: 99%

Extracellular matrix and integrin signalling: the shape of things to come

Boudreau

Jones

1999

Biochemical Journal

421

139

View full text Add to dashboard Cite

The extracellular matrix (ECM) and integrins collaborate to regulate gene expression associated with cell growth, differentiation and survival. Biochemical and molecular analyses of integrin signalling pathways have uncovered several critical cytoplasmic proteins that link the ECM and integrins to intracellular pathways that may contribute to anchorage-dependent growth. A large body of evidence now indicates that the non-receptor protein kinases focal adhesion kinase (FAK) and specific members of the mitogen-activated protein kinases (MAPKs), including the extracellular-signal-regulated kinases (ERKs), mediate these ECM- and integrin-derived signalling events. However, little is known about how FAK and MAPKs contribute to biological processes other than cell proliferation or migration. In addition, remarkably little is known concerning the signalling events that occur in cells that adhere to complex multivalent extracellular matrices via multiple integrin receptors. Given the stringent requirement for attaining a proper morphology in ECM/integrin-directed cell behaviour, it is still not clear how cell shape and tissue architecture impact upon intracellular signalling programmes involving FAK and MAPKs. However, the recent discovery that members of the Rho family of small GTPases are able to regulate ECM/integrin pathways that modulate both cell shape and intracellular signalling provides new insights into how cell morphology and signal transduction become integrated, especially within three-dimensional differentiated tissues.

show abstract

Section: Fakmentioning

confidence: 99%

Extracellular matrix and integrin signalling: the shape of things to come

Boudreau

Jones

1999

Biochemical Journal

421

139

View full text Add to dashboard Cite

show abstract

“…These conformational changes are associated with a dramatic change in the quaternary structure of the integrin, resulting in a switch from a "bent" conformation observed in the crystal structure (37) to an extended one (38) that features a C-terminal separation (39) that would disrupt the TM helical packing proposed here. This disruption could lead to the changes in the intracellular interactions of occupied integrins manifested by focal adhesion targeting and transdominant inhibition (34,40). Furthermore, the work of Li et al (10) shows that isolated integrin ␣ and ␤ TM peptides homooligomerize, a process that could contribute to integrin clustering.…”

Section: Figmentioning

confidence: 99%

Transmembrane Domain Helix Packing Stabilizes Integrin αIIbβ3 in the Low Affinity State

Partridge

Liu²,

Kim

et al. 2005

Journal of Biological Chemistry

141

161

View full text Add to dashboard Cite

Regulated changes in the affinity of integrin adhesion receptors ("activation") play an important role in numerous biological functions including hemostasis, the immune response, and cell migration. Physiological integrin activation is the result of conformational changes in the extracellular domain initiated by the binding of cytoplasmic proteins to integrin cytoplasmic domains. The conformational changes in the extracellular domain are likely caused by disruption of intersubunit interactions between the ␣ and ␤ transmembrane (TM) and cytoplasmic domains. Here, we reasoned that mutation of residues contributing to ␣/␤ interactions that stabilize the low affinity state should lead to integrin activation. Thus, we subjected the entire intracellular domain of the ␤3 integrin subunit to unbiased random mutagenesis and selected it for activated mutants. 25 unique activating mutations were identified in the TM and membrane-proximal cytoplasmic domain. In contrast, no activating mutations were identified in the more distal cytoplasmic tail, suggesting that this region is dispensable for the maintenance of the inactive state. Among the 13 novel TM domain mutations that lead to integrin activation were several informative point mutations that, in combination with computational modeling, suggested the existence of a specific TM helix-helix packing interface that maintains the low affinity state. The interactions predicted by the model were used to identify additional activating mutations in both the ␣ and ␤ TM domains. Therefore, we propose that helical packing of the ␣ and ␤ TM domains forms a clasp that regulates integrin activation.Integrin heterodimers are essential for the development and functioning of multicellular animals, because they mediate cell migration and cell adhesion and can influence gene expression and cell proliferation (1). All of the integrin heterodimers are composed of single pass Type I transmembrane (TM) 1 protein subunits ␣ and ␤. A central feature of these receptors is their capacity for rapid changes in their adhesive function mediated by changes in their ligand binding affinity, operationally defined here as "activation." The prototypical integrin, platelet ␣IIb␤3, is activated through interactions of the cytoplasmic integrin tails (ϳ20 and 47 residues for ␣ and ␤ tails, respectively) with intracellular proteins such as talin (2). These interactions initiate a long-range conformational change in the large extracellular domains (Ͼ700 residues each), resulting in high affinity binding of fibrinogen, von Willebrand factor, and fibronectin and consequently platelet aggregation and adherence to the vessel wall (1).Initial mutational studies suggested that a salt bridge between ␣IIbArg 995 and ␤3Asp 723 helps maintain the integrin in the low affinity state by forming part of an interactive face between ␣ and ␤ subunit cytoplasmic domains (3). Protein engineering studies from Springer laboratory have further advanced the idea that specific integrin ␣/␤ interactions maintain the low affinity conform...

show abstract

“…All cell lines were maintained in culture in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, glutamine, penicillin, streptomycin (Biological Industries, Beit Ha'emek, Israel), and 1 mM sodium pyruvate (Sigma). Electroporation of these cells with 30 g of DNA for each chimeric IL-2R/cytoplasmic protein construct was performed as described previously at 170 V and 960 microfarads with a Bio-Rad Gene Pulser but without any thymidine block (22). Some transfections were performed using LipofectAMINE Plus (Invitrogen) utilizing standard protocols.…”

Section: Construction Of Chimericmentioning

confidence: 99%

“…The sequences of all constructs were confirmed by nucleotide sequencing, and protein expression from the constructs described in this study was confirmed following transfection by both immunofluorescence staining and Western immunoblotting. The general approach to generate a chimera with each type of cytoplasmic domain was to insert partial or full-length cDNA molecules into HindIII-XhoI or HindIII-XbaI restriction sites of the plasmid vector pCMV/IL-2R (22). This vector is driven by the CMV promoter, and it expresses the extracellular and transmembrane domains of the non-signaling ␣ subunit of the interleukin-2 receptor (IL-2R) as a fusion protein with any molecule of interest as the cytoplasmic domain, as illustrated in Fig.…”

Section: Construction Of Chimericmentioning

confidence: 99%

Targeting Membrane-localized Focal Adhesion Kinase to Focal Adhesions

Katz

Romer

Miyamoto

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

In the present study, we examined regulation of activated focal adhesion kinase localization in focal adhesions. By using focal adhesion kinase fused to an inert transmembrane anchor, we found that the focal contact targeting region within focal adhesion kinase was preserved in the membrane-targeted fusion protein. However, upon tyrosine phosphorylation, full-length focal adhesion kinase became excluded from focal adhesions. This negative regulation of localization could be abolished by mutating key amino acid residues of focal adhesion kinase shown previously to be involved in adhesion-mediated signal transduction. Hyper-phosphorylation of endogenous focal adhesion kinase induced by pervanadate resulted in a similar reduction of localization at focal adhesions. We also show here that Src family kinases are essential for the phosphorylation-dependent exclusion of focal adhesion kinase from focal adhesions. We propose here a molecular model for the tyrosine phosphorylation-dependent regulation of focal adhesion kinase organization involving Src kinases and an inhibitory phosphorylation of the C-terminal (Tyr-925) tyrosine residue.Adhesion-mediated signaling triggers tyrosine phosphorylation of a multitude of proteins, including paxillin, tensin, and focal adhesion kinase (FAK) 1 (1-4). FAK phosphorylation following adhesion depends on its association with Src family kinases, leading to the formation of multimolecular signaling complexes in which FAK serves as a scaffold (5-7). Following activation, residue Tyr-397 of FAK becomes auto-phosphorylated, resulting in the formation of an SH2-docking site (5). Src family kinases then associate with Tyr-397 and phosphorylate several other tyrosine residues in FAK, including Tyr-925 that resides within the focal adhesion targeting (FAT) sequence at the FAK C terminus (5). The adaptor protein Grb2 then binds phosphorylated Tyr-925 and forms a signaling complex that includes the nucleotide exchange factor Sos and the small GTP-binding protein Ras (5). This sequence of events contributes to activation of the ERK1/2 response (5). Two additional pathways lead to FAK-mediated activation of ERK1/2: one involves binding of the adaptor protein p130 Cas to the prolinerich region of FAK via an SH3 domain interaction, and the second is the result of FAK association with the adaptor protein Shc (8 -10).The mechanisms that underlie FAK activation are not yet clear. Although FAK lacks any myristoylation or farnesylation signals, membrane translocation of FAK could be initiated by direct association with the ␤ 1 integrin tail (11). Close indirect interaction between FAK and integrin cytoplasmic tails may also be mediated via talin or paxillin (12, 13). Indeed, several studies (11,14) have demonstrated that a membrane-translocated form of FAK (following fusion to an inert transmembrane anchor) results in an adhesion-independent, constitutive phosphorylation of the molecule. This phosphorylated state of FAK depends on its association with Src and is accompanied by constitutive association ...

show abstract

Regulation of fibronectin receptor distribution [published erratum appears in J Cell Biol 1992 Jul;118(2):491]

Cited by 266 publications

References 48 publications

Extracellular matrix and integrin signalling: the shape of things to come

Extracellular matrix and integrin signalling: the shape of things to come

Transmembrane Domain Helix Packing Stabilizes Integrin αIIbβ3 in the Low Affinity State

Targeting Membrane-localized Focal Adhesion Kinase to Focal Adhesions

Contact Info

Product

Resources

About