Regulation of Angiogenesis in Human Cancer via Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2)
Year: 2012
Type: book-chapter
Abstract: Regulation of Angiogenesis in Human Cancer viaVascular Endothelial Growth Factor Receptor-2 (VEGFR-2) 29 AKT as well as phospholipase C gamma (PLC-PKC-MEK)]; Y 1214 (p38MAPK-HSP27) [(for Review see (Olsson et al. 2006;Rahimi 2006)].pY 951 VEGFR-2 (in the kinase insert domain) was recently found to increase angiogenesis (Tahir et al. 2009b) and seems to be also important for the interaction between VEGFR-2, PI-3K and PLC , which involves the adapter protein VEGF receptor-associated protein (VRAP also known as TSAd) (Wu et al. 2000).Other putatively important phosphorylated sites include Y 996 in the kinase insert domain and Y 1054 and Y 1059 in the tyrosine kinase catalytic domain.These tyrosine residues, together with Y 951 , when phosphorylated, act as docking sites to recruit molecules containing SH2, SH3 or PTB domains and to convey signals to downstream pathways (Petrova et al. 1999).Sequential activation of CDC42 and p38 MAPK by pY 1214 (or Y 1212 in mice) VEGFR-2 has been implicated in VEGF-induced actin remodeling (Lamalice et al. 2004).On the other hand, the upstream phosphorylation of Y 801 within the juxtamembrane domain of VEGFR-2 seems to be required for the subsequent activation of the catalytic domain.However, the biological implications of these findings need to be further investigated (Solowiej et al. 2009).Moreover, human Y 801 and 1175 VEGFR-2 (Y 799 and 1173 mouse) are required for binding/activation of PI-3K and EC growth but no for migration or PLC 1 activation (Dayanir et al. 2001).Additionally, pY 1054 and 1059 in the activation loop are essential for VEGF-induced intracellular Ca 2+ mobilization and the MAPK activation (Solowiej et al. 2009).However, the involvement of specific pY VEGFR-2 domains, activation of specific signaling pathways and driven functions is a point of controversial discussion (Guo et al. 2010).Recent data from Garonna et al., suggest that leptin (the major adipokine) treatment caused rapid phosphorylation of Y 1175 VEGFR-2.These leptin effects positively impacted on EC cell proliferation, survival and migration.Leptin-VEGFR-2 actions in EC involved a crosstalk between p38 kinase/Akt1 and COX-2 (Garonna et al. 2011).These leptin effects were detected in absence of VEGF.Leptin induces rapid (5 min) phosphorylation of pY 1175 VEGFR-2 in EC that was linked to proliferation, migration and tube formation in vitro (Garonna et al. 2011).We have also found leptin induces pY 951 VEGFR-2 in 4T1 mouse breast cancer cells.However, the biological significance of this finding need to be further investigated (Guo and Gonzalez-Perez, unpublished).In addition, specific serine residues in the VEGFR-2 cytoplasmatic region are targeted by protein kinase C (PKC) and involved in regulatory mechanisms of receptor levels (ubiquitinylation and degradation) (Singh et al. 2005).VEGF binding to VEGFR-2 triggers the specific activation of tyrosine amino acid residues within cytoplasmatic tail of the receptor inducing multiple signaling networks that result in EC survival, proliferation, migration, focal adhesion turnover, actin remodeling and vascular permeability (Kliche and Waltenberger 2001;Olsson et al. 2006;Zachary 2003).Signaling through mitogen-activated protein-kinase (MAP; including MEK-p42/p44MAPK and p38 MAPK; linked to proliferation) (Olsson et al. 2006;Takahashi and Shibuya 1997) and phosphatidylinositol 3' kinase (PI-3K)/V-akt murine thymoma viral oncogene homolog 1 (Akt1; linked to survival) (Abedi and Zachary 1997) are common receptor tyrosine kinase activation patterns.Additional signaling pathways are also triggered upon VEGFR-2 activation (i.e., PLC 1-PKC; linked to proliferation) ( Veikkola et al. 2000), focal adhesion kinase (linked to migration) (Abedi and Zachary 1997) and T Cell-Specific Adapter-Src kinase (linked to migration and vascular permeability) (Matsumoto et al. 2005) (See Fig 1).Overexpression of caveolin-1 in prostate cancer cells specifically induce pY 951 in the VEGFR-2 cytoplasmatic tail and increases angiogenesis (Tahir et al. 2009a).On the other hand, Y 1175 mediates both PLC-1 and protein kinase A (PKA)-dependent signaling pathways required for VEGF-induced release of von Willebrand factor from EC (Xiong et al. 2009).Dayanir et al, found that activation of PI-3K/S6 but not Ras/MAPK kinase pathway is responsible for www.intechopen.com
Source: InTech eBooks
DOI: 10.5772/27370
Authors: Shanchun Guo, Laronna S., Tanisha Z., Ruben R.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W1494565731