Role of the cytoplasmic tyrosines of β1A integrins in transformation by v-src

Sakai, Takao; Jove, Richard; Fässler, Reinhard; Mosher, Deane F.

doi:10.1073/pnas.240456398

Cited by 69 publications

(80 citation statements)

References 34 publications

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“…1D). This lower level of v-Src-stimulated haptotaxis is consistent with studies showing that v-Src phosphorylation of integrins inhibited in vitro cell migration compared with normal cells (22). Since a fully transformed cell phenotype encompasses changes in the growth, motility, and invasive property of cells, the reconstituted SrcϪ/Ϫ cells were analyzed for the acquisition of an invasive phenotype.…”

Section: Comparisons Of V-src Isoforms With Either Trp-95 or Arg-95supporting

confidence: 84%

v-Src SH3-enhanced Interaction with Focal Adhesion Kinase at β1 Integrin-containing Invadopodia Promotes Cell Invasion

Hauck

Hsia

Ilić

et al. 2002

Journal of Biological Chemistry

106

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In viral Src (v-SrcCrystal structure analyses revealed that the v-Src SH3 domain mutations were within the RT loop and were near the surface ligand binding groove (5). Substitution of murine c-Src RT loop residues (Trp at Arg-97 and Ile at Thr-98) did not disrupt the binding of normal c-Src SH3 targets such as p130Cas (6). Instead, RT loop residue changes at Trp-97 promoted the binding of proteins such as connexin 43 and FAK to the c-Src SH3 domain (6, 7). In FAK, the v-Src SH3 domain binding sites were mapped to three proline-rich motifs conforming to a PXXPXX consensus where is a hydrophobic residue (6). This extended PXXPXX motif differs from c-Src class I or class II SH3 binding motifs (5) and is conserved in other v-Src SH3 domain-binding proteins (7,8). Since the v-Src SH3 domain binds to additional targets compared with the c-Src SH3 domain, the RT loop substitutions can be considered gain-of-function mutations.

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Section: Comparisons Of V-src Isoforms With Either Trp-95 or Arg-95supporting

confidence: 84%

v-Src SH3-enhanced Interaction with Focal Adhesion Kinase at β1 Integrin-containing Invadopodia Promotes Cell Invasion

Hauck

Hsia

Ilić

et al. 2002

Journal of Biological Chemistry

106

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Section: Integrins and Cadherinsmentioning

confidence: 99%

“…At the integrin level, v-Src has been shown to influence integrin function by direct phosphorylation of tyrosine residues or via indirect phosphorylation of R-Ras (Sakai et al, 2001;Zou et al, 2002). V-Src-mediated phosphorylation of b1A integrin was found to occur on tyrosines 783 and 795 (Sakai et al, 2001). V-Src expression induced a reduction in adhesion of cells expressing wild-type b1A integrin, but could less effectively impair adhesion of cells expressing a b1A variant with both of these tyrosine residues mutated to phenylalanine (Datta et al, 2001).…”

Section: Integrins and Cadherinsmentioning

confidence: 99%

The interplay between Src and integrins in normal and tumor biology

2004

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Src family nonreceptor protein tyrosine kinases transduce signals that control normal cellular processes such as cell proliferation, adhesion and motility. Normally, cellular Src is held in an inactive state, but in several cancer types, abnormal events lead to elevated kinase activity of the protein and cause pleiotropic cellular responses inducing transformation and metastasis. A prerequisite of the ability of a cancer cell to undergo metastasis into distant tissues is to penetrate surrounding extracellular matrices. These processes are facilitated by the integrin family of cell adhesion molecules. As is the case with Src, altered integrin activity or substrate affinity can contribute to the neoplastic phenotype. Therefore, understanding the interplay between Src and integrin function has been of intense interest over the past few years. This review focuses on the role of Src and integrin signaling in normal cells and how this is deregulated in human cancer. We will identify the key players in the integrin-mediated signaling pathways involved in cell motility and apoptosis, such as FAK, paxillin and p130 CAS , and discuss how Src signaling affects the formation of focal adhesions and the extracellular matrix.

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“…Tyrosine phosphorylation of the NPXY motifs in integrin ␤ tails by Src family kinases is important in cell migration (41), hemostasis (42), and transformation (43). PTB domain recognition of peptide ligands can be promoted or inhibited by NPXY phosphorylation (21).…”

Section: Molecular Modeling and Mutagenesis Establish That Integrin ␤mentioning

confidence: 99%

Integrin β cytoplasmic domain interactions with phosphotyrosine-binding domains: A structural prototype for diversity in integrin signaling

Calderwood

Fujioka

Pereda

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

379

344

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The cytoplasmic domains (tails) of heterodimeric integrin adhesion receptors mediate integrins' biological functions by binding to cytoplasmic proteins. Most integrin ␤ tails contain one or two NPXY͞F motifs that can form ␤ turns. These motifs are part of a canonical recognition sequence for phosphotyrosine-binding (PTB) domains, protein modules that are present in a wide variety of signaling and cytoskeletal proteins. Indeed, talin and ICAP1-␣ bind to integrin ␤ tails by means of a PTB domain-NPXY ligand interaction. To assess the generality of this interaction we examined the binding of a series of recombinant PTB domains to a panel of short integrin ␤ tails. In addition to the known integrin-binding proteins, we found that Numb (a negative regulator of Notch signaling) and Dok-1 (a signaling adaptor involved in cell migration) and their isolated PTB domain bound to integrin tails. Furthermore, Dok-1 physically associated with integrin ␣IIb␤3. Mutations of the integrin ␤ tails confirmed that these interactions are canonical PTB domain-ligand interactions. First, the interactions were blocked by mutation of an NPXY motif in the integrin tail. Second, integrin class-specific interactions were observed with the PTB domains of Dab, EPS8, and tensin. We used this specificity, and a molecular model of an integrin ␤ tail-PTB domain interaction to predict critical interacting residues. The importance of these residues was confirmed by generation of gain-and loss-of-function mutations in ␤7 and ␤3 tails. These data establish that short integrin ␤ tails interact with a large number of PTB domain-containing proteins through a structurally conserved mechanism. I ntegrin adhesion receptors are heterodimers of ␣ and ␤ subunits, which combine to form a large extracellular domain, two transmembrane domains (one for each subunit), and a cytoplasmic domain typically composed of the short ␣ and ␤ C-terminal cytoplasmic tails (1). Bidirectional signal transduction through integrin adhesion receptors is essential for a wide variety of functions, including cell adhesion and migration, and assembly and remodeling of the extracellular matrix. Binding of intracellular proteins to integrin cytoplasmic tails is an important step in the transduction of signals to and from integrin-adhesion receptors (2). Integrin ␤ cytoplasmic tails, with the exception of those of ␤4 and ␤8, are short (Ͻ60 residues) and contain one or two NPXY or NPXY-like motifs (Fig. 1A), the first of which has the propensity to form a ␤ turn (3). Such ␤ turn-forming sequences frequently serve to bind to phosphotyrosine-binding (PTB) domains (4). NXXY motif-dependent binding of the Shc PTB domain to the large (Ͼ1,000 residues) ␤4 cytoplasmic tail has been observed (5) and molecular modeling studies suggested that the interaction of integrin cytoplasmic domain-associated protein (ICAP)1-␣ with ␤1A (6), and of talin with ␤3 (7), are mediated by PTB domain-like interactions. The solved crystal structure of a complex of a talin fragment with part of the ␤3 tail verified th...

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Role of the cytoplasmic tyrosines of β1A integrins in transformation by v-src

Cited by 69 publications

References 34 publications

v-Src SH3-enhanced Interaction with Focal Adhesion Kinase at β1 Integrin-containing Invadopodia Promotes Cell Invasion

v-Src SH3-enhanced Interaction with Focal Adhesion Kinase at β1 Integrin-containing Invadopodia Promotes Cell Invasion

The interplay between Src and integrins in normal and tumor biology

Integrin β cytoplasmic domain interactions with phosphotyrosine-binding domains: A structural prototype for diversity in integrin signaling

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