Tyrosine phosphorylation of missing in metastasis protein is implicated in platelet-derived growth factor-mediated cell shape changes.
Missing in metastasis gene, or MTSS1, encodes an intracellular protein that is implicated in actin cytoskeleton reorganization and often down-regulated in certain types of tumor cells. In response to platelet-derived growth factor (PDGF), green fluorescent protein (GFP)-tagged murine Mtss1 (Mtss1-GFP) underwent redistribution from the cytoplasm to dorsal membrane ruffles along with phosphorylation at tyrosine residues in a time-dependent manner. Tyrosine phosphorylation of Mtss1-GFP was also elevated in cells where an oncogenic Src was activated but severely impaired in Src knock-out cells or cells treated with Src kinase inhibitor PP2. Mutagenesis analysis has revealed that phosphorylation occurs at multiple sites, including tyrosine residues Tyr-397 and Tyr-398. Mutation at both Tyr-397 and Tyr-398 abolished the PDGF-mediated tyrosine phosphorylation. Furthermore, recombinant Mtss1 protein was phosphorylated by recombinant Src in a manner dependent on Tyr-397 and Tyr-398. Efficient tyrosine phosphorylation of Mtss1 in response to PDGF also involves a coiled-coil domain, which is essential for a proper distribution to the cell leading edge and dorsal ruffles. Interestingly, overexpression of wild type Mtss1-GFP promoted the PDGF-induced dorsal ruffling, whereas overexpression of a mutant deficient in phosphorylation at Tyr-397 and Tyr-398 or a mutant with deletion of the coiled-coil domain impaired the formation of dorsal ruffles. These data indicate that Mtss1 represents a novel signaling pathway from PDGF receptor to the actin cytoskeleton via Src-related kinases.
Wang
Ying
Y
Department of Pathology, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Center for Vascular and Inflammatory Diseases, Baltimore, Maryland 21201, USA.
Zhou
Kang
K
Zeng
Xianchun
X
Lin
Jinxiu
J
Zhan
Xi
X
D000818:Animals; D048430:Cell Shape / Q000187:drug effects*; D051379:Mice; D008840:Microfilament Proteins / Q000737:chemistry / Q000502:physiology*; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000737:chemistry / Q000502:physiology*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*; D019061:src-Family Kinases / Q000502:physiology
D008840:Microfilament Proteins; C473219:Mtss1 protein, mouse; D009363:Neoplasm Proteins; D010982:Platelet-Derived Growth Factor; D014443:Tyrosine; D019061:src-Family Kinases