VEGF–integrin interplay controls tumor growth and vascularization

De, Sajal; Razorenova, Olga V.; McCabe, N. Patrick; O’Toole, Timothy E.; Qin, Jun; Byzova, Tatiana V.

doi:10.1073/pnas.0502935102

Cited by 169 publications

(119 citation statements)

References 30 publications

(27 reference statements)

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“…Intestinal smooth muscle cells express ␣V␤3, and blocking ligand occupancy of this integrin inhibits IGF-I actions (45). Endothelial cells have abundant ␣V␤3, which can function to localize Shc to the cell membrane (41,46), and our studies have shown that blocking ligand occupancy of endothelial ␣V␤3 attenuates IGF-I-stimulated Shc activation and cell growth. Skeletal unloading results in decreased ␣V␤3 expression in osteoblasts, and they become refractory to stimulation of the MAP kinase pathway activation and growth by IGF-I (47).…”

Section: Discussionmentioning

confidence: 99%

The Role of Src Kinase in Insulin-like Growth Factor-dependent Mitogenic Signaling in Vascular Smooth Muscle Cells

Lieskovská

Ling

Badley-Clarke

et al. 2006

Journal of Biological Chemistry

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Activation of the MAPK pathway mediates insulin-like growth factor-I (IGF-I)-dependent proliferation in vascular smooth muscle cells (SMC).Our previous studies have shown that IGF-I-induced Shc phosphorylation is necessary for sustained activation of MAPK and increased cell proliferation of SMCs, and both Shc and the tyrosine phosphatase SHP-2 must be recruited to the membrane protein SHPS-1 in order for Shc to be phosphorylated. These studies were undertaken to determine whether Src kinase activity is required to phosphorylate Shc in response to IGF-I in SMC and because SHP-2 binds to Src whether their interaction was also required for IGF-I-stimulated mitogenesis. Our results show that IGF-I induces activation of Src kinase and that is required for Shc phosphorylation and for optimal MAPK activation. We tested whether Shc is a substrate of c-Src in SMC by disrupting Src/Shc association using a peptide containing a YXXL (Tyr 328 ) motif sequence derived from Src. The peptide blocked the binding of Src and Shc in vitro and in vivo. Cells expressing a mutant Src (Src-FF) that had Tyr 328 / Tyr 358 substituted with phenylalanines (Src-FF) showed defective Src/Shc binding, impaired IGF-I-dependent Shc phosphorylation, and impaired mitogenesis. This supports the conclusion that Src phosphorylates Shc. IGF-I induced both Src/SHP-2 and Src/SHPS-1 association. SMCs expressing an SHP-2 mutant that had the polyproline-rich region of SH2 deleted (SHP-2⌬10) had disrupted SHP-2/Src association, impaired IGF-I-dependent Shc phosphorylation, and an attenuated mitogenic response. IGF-I-induced association of Src and SHPS-1 was also impaired in SHP-2⌬10-expressing cells, although SHP-2/SHPS-1 association was unaffected. Upon IGF-I stimulation, a complex assembles on SHPS-1 that contains SHP-2, c-Src, and Shc wherein Src phosphorylates Shc, a signaling step that is necessary for an optimal mitogenic response. IGF-I2 stimulation of vascular smooth muscle cells (SMC) leads to activation of two major signaling pathways, e.g. the MAP kinase (MAPK) and PI 3-kinase pathways (1). Activation of the MAPK pathway is required for IGF-I-dependent proliferation, whereas activation of the PI 3-kinase pathway is the predominant determinant of IGF-I-dependent SMC migration. BindingofIGF-ItotheIGF-Ireceptorleadstoreceptorautophosphorylation followed by tyrosine phosphorylation of substrates such as IRS-1 and Shc (2). These adaptor proteins bind Grb2/ SOS and activate the Ras/MAPK pathway (3). Previous studies in SMC have shown that IGF-I-induced Shc phosphorylation and its association with Grb-2 are necessary for sustained phosphorylation of Erk1/2 MAPK and IGF-I-dependent cell proliferation (4). The requirement of Shc phosphorylation for growth factor-dependent mitogenesis has been demonstrated in other cell types as well (5, 6).Src family kinases (SFK) have been implicated in mediating the mitogenic effect of several growth factors (7, 8); however, the mechanism by which SFK function is not completely understood. Src has also been implicated i...

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Section: Discussionmentioning

confidence: 99%

The Role of Src Kinase in Insulin-like Growth Factor-dependent Mitogenic Signaling in Vascular Smooth Muscle Cells

Lieskovská

Ling

Badley-Clarke

et al. 2006

Journal of Biological Chemistry

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“…These observations are in accord with our previous studies demonstrating that VEGF is a potent stimulator of the ␣V␤3 activation and ␣V␤3-dependent EC functions via VEGFR2-dependent inside-out signaling. 6,7 Thus, the kindlin-2 ϩ/Ϫ phenotype demonstrates a critical role of ␤3 integrins in angiogenesis in vivo in the absence of compensatory increases in VEGFR2. However, kindlin-2 also promotes the ␤3 integrin functions via other inside-out signaling pathways, for example, PKC-dependent For personal use only.…”

Section: Discussionmentioning

confidence: 99%

“…6 Indeed, VEGFR2 and integrin ␣V␤3 can form a physical complex in EC and influence the functions of each other. 6,7 Two sets of cytoskeletal proteins, the talins and the kindlins, bind to the ␤ cytoplasmic tails and are now known to be involved in integrin activation. [8][9][10] Talin has long been known to be critical for integrin activation 11 and more recent studies have shown an obligatory requirement for the kindlins in integrin activation in the context of intact cells and whole organisms.…”

Section: Introductionmentioning

confidence: 99%

The integrin coactivator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish

Pluskota

Dowling

Gordon

et al. 2011

Blood

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Kindlin-2, a widely distributed cytoskeletal protein, has been implicated in integrin activation, and its absence is embryonically lethal in mice and causes severe developmental defects in zebrafish. Knockdown of kindlin-2 levels in endothelial cells resulted in defective adhesive and migratory responses, suggesting that angiogenesis might be aberrant even with partial reduction of kindlin-2. This hypothesis has now been tested in the kindlin-2 ؉/؊ mice. RM1 prostate tumors grown in kindlin-2 ؉/؊ mice had fewer blood vessels, which were thinner and shorter and supported less tumor growth compared with wild-type littermates. The vessels that did form in the kindlin-2 ؉/؊ mice lacked smooth muscle cells and pericytes and had thinner basement membranes, indicative of immature vessels. VEGF-induced angiogenesis in matrigel implants was also abnormal in the kindlin-2 ؉/؊ mice. Vessels in the kindlin-2 ؉/؊ mice were leaky, and BM transplantation from kindlin-2 ؉/؊ to WT mice did not correct this defect. Endothelial cells derived from kindlin-2 ؉/؊ mice had integrin expression levels similar to WT mice but reduced ␣V␤3-dependent signaling, migration, adhesion, spreading, and tube formation. Developmental angiogenesis was markedly impaired by kindlin-2 morpholinos in zebrafish. Taken together, kindlin-2 plays an important role in pathologic and developmental angiogenesis, which arises from defective activation of integrin ␣V␤3. IntroductionAlthough endothelial cells (ECs) are the primary cell type that forms blood vessel tubes, other cell types, including BM-derived cells, smooth muscle cells, and pericytes, are all engaged in forming blood-bearing conduits. Growth factor-growth factor receptor interactions are involved in initial recruitment of these cells while other ligand-receptor systems govern migration of the responding cells into angiogenic tissues (reviewed in Folkman 1 ). Among the cellular receptors that specialize in regulating the adhesive and migratory responses of cells during angiogenesis are members of the integrin family. 2 Integrins of the ␤1 and ␤3 subfamilies on ECs have been implicated in angiogenesis in vivo through knockout 3 and inhibitor approaches 4 and integrin ␣V␤3 and ␣5␤1 are targets of antiangiogenic drugs for cancer treatment (reviewed in Avraamides et al 5 ).The regulation of integrin function in angiogenesis as well as many other responses depends on their ability to undergo activation, a rapid transition from a low-to a high-affinity state for recognition of their ligands. Particularly relevant to angiogenesis is the ability of VEGF to activate integrin ␣V␤3 and ␣5␤1 by engaging one of its EC receptors, VEGFR2. 6 Indeed, VEGFR2 and integrin ␣V␤3 can form a physical complex in EC and influence the functions of each other. 6,7 Two sets of cytoskeletal proteins, the talins and the kindlins, bind to the ␤ cytoplasmic tails and are now known to be involved in integrin activation. [8][9][10] Talin has long been known to be critical for integrin activation 11 and more recent studies have sh...

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“…VEGF is known to exert an autocrine as well as paracrine mitogenic effect on a variety of tumor cells including melanoma, prostate cancer, and ovarian cancer in vivo (22,(35)(36)(37)(38). Our pilot studies indicated that VEGF stimulates the proliferation of ID8 cells in a concentration-dependent manner (data not shown).…”

Section: Sparc Inhibits Vegf-induced Proliferation and Survival Of Ovmentioning

confidence: 99%

Normalization of the Ovarian Cancer Microenvironment by SPARC

Said¹,

Socha²,

Olearczyk³

et al. 2007

Molecular Cancer Research

102

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VEGF–integrin interplay controls tumor growth and vascularization

Cited by 169 publications

References 30 publications

The Role of Src Kinase in Insulin-like Growth Factor-dependent Mitogenic Signaling in Vascular Smooth Muscle Cells

The Role of Src Kinase in Insulin-like Growth Factor-dependent Mitogenic Signaling in Vascular Smooth Muscle Cells

The integrin coactivator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish

Normalization of the Ovarian Cancer Microenvironment by SPARC

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