title: The MLK-related kinase (MRK) is a novel RhoC effector that mediates lysophosphatidic acid (LPA)-stimulated tumor cell invasion.
abstract: The small GTPase RhoC is overexpressed in many invasive tumors and is essential for metastasis. Despite its high structural homology to RhoA, RhoC appears to perform functions that are different from those controlled by RhoA. The identity of the signaling components that are differentially regulated by these two GTPases is only beginning to emerge. Here, we show that the MAP3K protein MRK directly binds to the GTP-bound forms of both RhoA and RhoC in vitro. However, siRNA-mediated depletion of MRK in cells phenocopies depletion of RhoC, rather than that of RhoA. MRK depletion, like that of RhoC, inhibits LPA-stimulated cell invasion, while depletion of RhoA increases invasion. We also show that active MRK enhances LPA-stimulated invasion, further supporting a role for MRK in the regulation of invasion. Depletion of either RhoC or MRK causes sustained myosin light chain phosphorylation after LPA stimulation. In addition, activation of MRK causes a reduction in myosin light chain phosphorylation. In contrast, as expected, depletion of RhoA inhibits myosin light chain phosphorylation. We also present evidence that both RhoC and MRK are required for LPA-induced stimulation of the p38 and ERK MAP kinases. In conclusion, we have identified MRK as a novel RhoC effector that controls LPA-stimulated cell invasion at least in part by regulating myosin dynamics, ERK and p38.
authors: Oncology and Cell Biology Center, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
authors: Olga
authors: O
authors: Korkina
authors: Zhiwan
authors: Z
authors: Dong
authors: Allison
authors: A
authors: Marullo
authors: Gregg
authors: G
authors: Warshaw
authors: Marc
authors: M
authors: Symons
authors: Rosamaria
authors: R
authors: Ruggieri
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D005260:Female; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007797:Laminin / Q000737:chemistry; D008246:Lysophospholipids / Q000378:metabolism*; D008954:Models, Biological; D009218:Myosins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000502:physiology*; D011509:Proteoglycans / Q000737:chemistry; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000075024:rhoC GTP-Binding Protein
chemical_list: D004338:Drug Combinations; D007797:Laminin; D008246:Lysophospholipids; D011509:Proteoglycans; C059485:matrigel; C066737:RHOA protein, human; D003094:Collagen; C097276:CILK1 protein, human; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D009218:Myosins; D044365:GTP-Binding Protein alpha Subunits, G12-G13; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein; C032881:lysophosphatidic acid