The Tumor Suppressor DAPK Is Reciprocally Regulated by Tyrosine Kinase Src and Phosphatase LAR
Journal
Molecular Cell
Journal Volume
27
Journal Issue
5
Pages
701-716
Date Issued
2007
Author(s)
Wang W.-J.
Kuo J.-C.
Ku W.
Lee Y.-R.
Lin F.-C.
Lin Y.-M.
Chen C.-H.
Huang Y.-P.
Chiang M.-J.
Yeh S.-W.
Wu P.-R.
Shen C.-H.
Chen R.-H.
Abstract
Death-associated protein kinase (DAPK) is a calmodulin-regulated serine/threonine kinase and elicits tumor suppression function through inhibiting cell adhesion/migration and promoting apoptosis. Despite these biological functions, the signaling mechanisms through which DAPK is regulated remain largely elusive. Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation. Upon EGF stimulation, a rapid Src activation leads to subsequent LAR downregulation, and these two events act in synergism to inactivate DAPK, thereby facilitating tumor cell migration and invasion toward EGF. Finally, DAPK Y491/492 hyperphosphorylation is found in human cancers in which Src activity is aberrantly elevated. These results identify LAR and Src as a DAPK regulator through their reciprocal modification of DAPK Y491/492 residues and establish a functional link of this DAPK-regulatory circuit to tumor progression. ? 2007 Elsevier Inc. All rights reserved.
SDGs
Other Subjects
CD45 antigen; death associated protein kinase; phosphatase; protein tyrosine kinase; small interfering RNA; tumor suppressor protein; tyrosine kinase src; unclassified drug; amino acid sequence; animal cell; apoptosis; article; cancer inhibition; catabolism; cell adhesion; cell differentiation; cell growth; controlled study; dephosphorylation; enzyme activation; enzyme activity; enzyme assay; enzyme regulation; human; human cell; immunoblotting; in vitro study; in vivo study; leukocyte migration inhibition test; nonhuman; protein expression; protein function; protein phosphorylation; protein protein interaction; signal transduction; tumor cell; Apoptosis Regulatory Proteins; Calcium-Calmodulin-Dependent Protein Kinases; Cell Line, Tumor; Epidermal Growth Factor; Humans; Neoplasms; Nerve Tissue Proteins; Phosphorylation; Protein Tyrosine Phosphatases; Proto-Oncogene Proteins pp60(c-src); Receptor-Like Protein Tyrosine Phosphatases, Class 2; Receptors, Cell Surface; Signal Transduction; Tumor Suppressor Proteins
Type
journal article