title: The tumor suppressor DAPK is reciprocally regulated by tyrosine kinase Src and phosphatase LAR.
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.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Won-Jing
authors.initials: WJ
authors.lastname: Wang
authors.forename: Jean-Cheng
authors.initials: JC
authors.lastname: Kuo
authors.forename: Wei
authors.initials: W
authors.lastname: Ku
authors.forename: Yu-Ru
authors.initials: YR
authors.lastname: Lee
authors.forename: Feng-Chi
authors.initials: FC
authors.lastname: Lin
authors.forename: Yih-Leong
authors.initials: YL
authors.lastname: Chang
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Lin
authors.forename: Chun-Hau
authors.initials: CH
authors.lastname: Chen
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Huang
authors.forename: Meng-Jung
authors.initials: MJ
authors.lastname: Chiang
authors.forename: Sheng-Wen
authors.initials: SW
authors.lastname: Yeh
authors.forename: Pei-Rung
authors.initials: PR
authors.lastname: Wu
authors.forename: Che-Hung
authors.initials: CH
authors.lastname: Shen
authors.forename: Chen-Tu
authors.initials: CT
authors.lastname: Wu
authors.forename: Ruey-Hwa
authors.initials: RH
authors.lastname: Chen
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism / Q000502:physiology*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D011956:Receptors, Cell Surface / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*