Integrins phosphorylation

R 351 S.C. Fagerholm, TJ. Hilden and C.G. Gahmberg, P Marks the Spot Site-Specific Integrin Phosphorylation Regulates Molecular Interactions , Trends Bio chem. Sci., 2004,29,504... 

Cohen-Hillel E, Yron I, Meshel T, Soria G, Attal H, Ben-Baruch A. CXCL8-induced FAK phosphorylation via CXCR1 and CXCR2 Cytoskeleton- and integrin-related mechanisms converge with FAK regulatory pathways in a receptor-specific manner. Cytokine 2006 33 1-16. 

The integrins do not have any enzyme activity in their own cytoplasmic domain, but on hgand binding, stimulation of tyrosine phosphorylation is observed on the cytoplasmic side of many cells, such as fibroblasts and platelets. The exact configuration of protein-protein interactions on the cytosolic side of the integrins is not clear and the mechanism of stimulation of protein tyrosine kinases is unknown. Some components of the focal adhesion points, such as the structural protein tensin, have SH2 and SH3 domains that may serve as specific attachment points for tyrosine kinases and other signal proteins. 

Raman spectroscopy has been successfully used to detect nanomolar concentrations of biologically relevant molecules, to distinguish between structurally similar peptides (e.g. aEp3 and a5pi integrins [22]) and also to detect peptide S-nitrosylation and phosphorylation [23, 24]. Raman spectroscopy has been used to determine the functionalisation of carbon nanotubes and other particles with bioactive peptides (e.g. RGD), whereby their biofunctionalisation has enabled their accumulation at specific sites (e.g. tumours) within small animal models [25]. Furthermore, the in vivo distribution and... 

Lee HS, Millward-Sadler SJ, Wright MO, Nuki G, Salter DM. 2000. Integrin and mechanosensitive ion channel-dependent tyrosine phosphorylation of focal adhesion proteins and beta-catenin in human articular chondrocytes after mechanical stimulation. J Bone Miner Res 15 1501-9. 

PGI2 exerts its inhibitory activity by increasing cyclic adenosine monophosphate (cAMP) formation via adenylate cyclase, which stimulates phosphorylation of a cytoskeleton integrin protein-associated vasodilator-stimulated phosphoprotein (VASP), which prevents GPIIb Ilia activation (16). 

A recently identified thyroid hormone cell surface receptor on the extracellular domain of integrin alphaVbeta (3) leads to the activation of the mitogen-activated protein kinase (MAPK) signal transduction cascade in human cell lines, Examples of MAPK-dependent thyroid hormone actions are plasma membrane ion pump stimulation and specific nuclear events, These events include serine phosphorylation of the nuclear thyroid hormone receptor, leading to co-activator protein recruitment and complex tissue responses, such as thyroid hormone-induced angiogenesis, The existence of this cell surface receptor means that the activity of the administered hormone could be limited through structural modification of the molecule to reproduce only those hormone actions initiated at the cell surface (8,9). 

Recently, it has been demonstrated that mechanical stress rapidly induced phosphorylation of PDGF receptor, activation of integrin receptor, stretch-activation of cation channels, and production of G proteins. Once mechanical stress was sensed, protein kinase C and MAPKs were activated, leading to increased c-fos and c-Jun gene expression and enhanced transcription factor AP-1 DNA binding activity. The application of physical forces also rapidly resulted in expression of MAPK phosphatase-1 (MKP-1), which inactivates MAPKs. 

Integrin betal null platelets from conditional knockout mice develop normally, platelet count is normal. Collagen induced platelet aggregation is delayed but otherwise normal tyrosine phosphorylation pattern is normal but phosphorylation is delayed. Bleeding time in bone marrow chimeric mice is normal no major in vivo defects (Nieswandt et al. 2001). 

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