Receptor-type Protein Tyrosine Phosphatase β (RPTP-β) Directly Dephosphorylates and Regulates Hepatocyte Growth Factor Receptor (HGFR/Met) Function

Abstract

Protein tyrosine phosphorylation is a ubiquitous, fundamental biochemical mechanism that regulates essential eukaryotic cellular functions. The level of tyrosine phosphorylation of specific proteins is finely tuned by the dynamic balance between protein tyrosine kinase and protein tyrosine phosphatase activities. Hepatocyte growth factor receptor (also known as Met), a receptor protein tyrosine kinase, is a major regulator of proliferation, migration, and survival for many epithelial cell types. We report here that receptor-type protein tyrosine phosphatase ␤ Hepatocyte growth factor (HGF)3 , also known as scatter factor, is expressed in numerous tissues (1-5) and participates in the regulation of angiogenesis, organogenesis, tissue repair, and neural induction (6). HGF induces random movement/scattering in epithelial cells as well as dissociation, migration, and invasion of cells through the extracellular matrix in vivo (7,8). HGF is mitogenic in many normal cell types, including epithelial cells, vascular endothelial cells, and melanocytes. HGF is also a morphogen that induces transition of epithelial cells into a mesenchymal morphology and formation of branched tubelike structures (9, 10). In keratinocytes, HGF has been shown to promote motility and proliferation (11,12). Each of these biological effects exerted by HGF is triggered by stimulation of its cell surface receptor, Met (also known as HGF receptor), with concomitant activation of downstream effecter molecules (8,13,14).Upon ligand binding, Met autophosphorylates several tyrosine residues in its carboxyl-terminal domain. Met function is controlled by its state of tyrosine phosphorylation (15-17). Among the tyrosines within the carboxyl terminus, phosphorylation of tyrosines 1234 and 1235, located within the catalytic domain, is required for tyrosine kinase activity (15-17). Phosphorylation of tyrosines 1349 and 1356, which are highly conserved among other members of the Met family, such as Sea and Ron, are necessary for most biological activities of . Tyrosines 1349 and 1356, when phosphorylated, serve as multifunctional binding sites for Gab1, Grab2, PI3K, phospholipase C-␥, SHP2, and Cbl proto-oncogene. Phosphorylation of tyrosine 1356 is essential for transducing signals for cell motility and morphogenesis (19 -21).In addition to its roles in many normal physiological processes, Met also plays important roles in human malignancy. Met was originally identified as the TPR-Met oncogene, which possesses ligand-independent tyrosine kinase activity. TPR-Met arises from chromosomal fusion of the translocated promoter region (TPR) in chromosome 1 with the Met carboxyl-terminal sequence on chromosome 7 (22, 23). This rearrangement has been observed in patients with gastric carcinoma (24). A large body of evidence demonstrates that misregulation of the Met signaling pathway is involved in many types of human cancers. Inappropriate expression of HGF/Met autocrine signaling confers increased tumorigenesis and metastatic activity in vivo, and Met expression o...

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Receptor‐type tyrosine phosphatase ligands: looking for the needle in the haystack

“…PTKs transmit extracellular signals and regulate various cellular process which are initiated through dimerization, induced by ligand‐binding, leading to autophosphorylation [89,90]. RPTPs can act as negative regulators of PTK signaling: for example, RPTPO ( RPTPO ) can diminish neurotrophin‐3‐induced TrkC phosphorylation [91], RPTPζ exerts an influence on TrkA [92,93], and RPTPβ ( PTPRB ) dephosphorylates its substrate Met, specifically at the binding site for several downstream effector molecules [94].…”

Expression of catalytically active matrix metalloproteinase‐1 in dermal fibroblasts induces collagen fragmentation and functional alterations that resemble aged human skin

“…Western blot was performed as previously described (Bank et al 1997; Xu et al 2011). Primary antibodies were incubated with PVDF membrane for one hour at room temperature, and immunoreactive protein bands were imaged and quantified by enhanced chemifluorescence, using a STORM Molecular Imager, with ImageQuant software (GE HealthCare, Piscataway, NJ).…”