Wang W.-J.Kuo J.-C.Ku W.Lee Y.-R.Lin F.-C.YIH-LEONG CHANGLin Y.-M.Chen C.-H.Huang Y.-P.Chiang M.-J.Yeh S.-W.Wu P.-R.Shen C.-H.CHEN-TU WUChen R.-H.2020-03-072020-03-0720071097-2765https://www.scopus.com/inward/record.uri?eid=2-s2.0-34548249520&doi=10.1016%2fj.molcel.2007.06.037&partnerID=40&md5=73b82ed317c111691d7f66ea7ec463eahttps://scholars.lib.ntu.edu.tw/handle/123456789/473869Death-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]SDG3CD45 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 Proteinsjournal article10.1016/j.molcel.2007.06.037178039362-s2.0-34548249520