Integrin and Growth Factor Receptor Crosstalk

Abstract

Abstract-Crosstalk between integrins and growth factor receptors are an important signaling mechanism to provide specificity during normal development and pathological processes in vascular biology. Evidence from several model systems demonstrates the physiological importance of the coordination of signals from growth factors and the extracellular matrix to support cell proliferation, migration, and invasion in vivo. Several examples of crosstalk between these two important classes of receptors indicate that integrin ligation is required for growth factor-induced biological processes. Furthermore, integrins can directly associate with growth factor receptors, thereby regulating the capacity of integrin/growth factor receptor complexes to propagate downstream signaling. Recent data suggest that antagonists of ␣ v integrins can provide a therapeutic benefit in human cancer patients, whereas knockout mice lacking specific integrins can provide an interesting insight into the role of integrins during development. This review will focus on the biological importance of integrin and growth factor receptor crosstalk that occurs during cell growth, migration, and invasion as well as in endothelial cells during angiogenesis. Key Words: integrins Ⅲ growth factor receptors Ⅲ cell migration/invasion Ⅲ angiogenesis R ecent work from a number of laboratories has demonstrated that cell adhesion receptors and growth factor receptors are important molecular determinants in providing specificity for signaling during development and/or during pathological processes. Although integrins and growth factor receptors can independently propagate intracellular signals, the synergy of signals provided by the extracellular matrix (ECM) and growth factors appears to regulate complex processes, including blood vessel development during embryogenesis as well as tumor growth/metastasis and angiogenesis in the adult. Analysis of the crosstalk between the biochemical pathways mediated by integrins and growth factor receptors may ultimately lead to a better understanding of the cell biological processes underlying normal development and the progression of pathological conditions. Several excellent reviews on integrin-mediated 1-4 and growth factor receptormediated signal transduction 5,6 have been recently published; therefore, this review will focus on the evidence for crosstalk between integrins and growth factor receptors in cell biology. These in vitro studies help provide an important insight into the role of integrins in more complex biological questions in vascular biology. This will be followed by an analysis of the recent progress on growth factor-induced angiogenesis as a paradigm for the study of the crosstalk between growth factor receptors and integrins in intact tissues. Recent work provides clinical data on the therapeutic benefit of ␣ v integrin antagonists, whereas studies of knockout mice, lacking various integrins, provide insight into the role of integrins during the embryonic development of the mouse vasculature. Model systems...

Differences in regulation of type I collagen synthesis in primary and passaged hepatic stellate cell cultures: the role of α5β1-integrin

“…A: CAT activity increases as HSC activation progresses. CAT was extracted at days 3,5,7,8,16,23, and 28 of the primary culture by harvesting cells followed by 3 cycles of freezing and thawing. CAT activity was determined by incorporation of [ 3 H]acetate from acetyl CoA into chloramphenicol as described in MATERIALS AND METHODS.…”

“…Previous studies have shown that DDR2, which binds type I collagen, is upregulated in activated HSC and its stimulation contributes to proliferation and invasiveness of activated HSC (32). In addition, type I collagen-and laminin-binding integrins have been reported to exist on HSC membrane and to mediate HSC proliferation and apoptosis (8).…”

“…Integrins are adhesion receptors located on the cell surface and the major membrane proteins involved in cell-ECM interactions (8). Each integrin is a heterodimer consisting of noncovalently bound ␣-and ␤-subunits.…”

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

“…The combination of different subunits originates distinct integrins that mediate cell adhesion to a variety of adhesive proteins of the ECM [133]. Integrins regulates also the response of endothelial cells to soluble growth factors, including FGF2 [134], but the molecular mechanism(s) of this regulation are not fully elucidated. a v b 3 integrin is expressed on endothelial cells where it plays a central role in neovascularization.…”

Soluble N-cadherin fragment promotes angiogenesis

“…Angiogenesis occurs in physiological (embryology, ovulation, wound healing) and in pathological situations (neoplasia, diabetic retinopathy, rheumatoid arthritis) [2]. The process is regulated by a balance between pro-and anti-angiogenic molecules, emanating from endothelial, stromal and epithelial cells [3], by comprising growth factors [4], proteinases [5] and their respective inhibitors [6], extracellular matrix molecules [7], and also by cell-cell and cell-substratum adhesion molecules [8].…”