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Intradomain cleavage of inhibitory prodomain is essential to protumorigenic function of membrane type-1 matrix metalloproteinase (MT1-MMP) in vivo.
Golubkov VS, Chernov AV, Strongin AY
J Biol Chem. 2011 Sep 30;286(39):34215-23
Potential relation of aberrant proteolysis of human protein tyrosine kinase 7 (PTK7) chuzhoi by membrane type 1 matrix metalloproteinase (MT1-MMP) to congenital defects.
Golubkov VS, Aleshin AE, Strongin AY
J Biol Chem. 2011 Jun 10;286(23):20970-6
The Wnt/planar cell polarity protein-tyrosine kinase-7 (PTK7) is a highly efficient proteolytic target of membrane type-1 matrix metalloproteinase: implications in cancer and embryogenesis.
Golubkov VS, Chekanov AV, Cieplak P, Aleshin AE, Chernov AV, Zhu W, Radichev IA, Zhang D, Dong PD, Strongin AY
J Biol Chem. 2010 Nov 12;285(46):35740-9
Internal cleavages of the autoinhibitory prodomain are required for membrane type 1 matrix metalloproteinase activation, although furin cleavage alone generates inactive proteinase.
Golubkov VS, Cieplak P, Chekanov AV, Ratnikov BI, Aleshin AE, Golubkova NV, Postnova TI, Radichev IA, Rozanov DV, Zhu W, Motamedchaboki K, Strongin AY
J Biol Chem. 2010 Sep 3;285(36):27726-36
Proteolysis of the membrane type-1 matrix metalloproteinase prodomain: implications for a two-step proteolytic processing and activation.
Golubkov VS, Chekanov AV, Shiryaev SA, Aleshin AE, Ratnikov BI, Gawlik K, Radichev I, Motamedchaboki K, Smith JW, Strongin AY
J Biol Chem. 2007 Dec 14;282(50):36283-91
Golubkov VS, Strongin AY
Cell Cycle. 2007 Jan 15;6(2):147-50
Membrane type-1 matrix metalloproteinase confers aneuploidy and tumorigenicity on mammary epithelial cells.
Golubkov VS, Chekanov AV, Savinov AY, Rozanov DV, Golubkova NV, Strongin AY
Cancer Res. 2006 Nov 1;66(21):10460-5
Centrosomal pericentrin is a direct cleavage target of membrane type-1 matrix metalloproteinase in humans but not in mice: potential implications for tumorigenesis.
Golubkov VS, Chekanov AV, Doxsey SJ, Strongin AY
J Biol Chem. 2005 Dec 23;280(51):42237-41
Membrane type-1 matrix metalloproteinase (MT1-MMP) exhibits an important intracellular cleavage function and causes chromosome instability.
Golubkov VS, Boyd S, Savinov AY, Chekanov AV, Osterman AL, Remacle A, Rozanov DV, Doxsey SJ, Strongin AY
J Biol Chem. 2005 Jul 1;280(26):25079-86
Vladislav Golubkov's Research Focus
Birth Defects, Cancer, Breast Cancer
Cell motility is implemented in diverse processes such as normal embryo development and cancer. Deregulated cell motility promotes congenital disorders, cancer progression and metastasis. Dr. Golubkov’s research is focused on understanding the molecular mechanisms regulating cell motility in pathology.
Vladislav Golubkov's Research Report
Recently, we identified a new mechanism that regulates directional cell motility. It is well established that matrix metalloproteases (MMPs), especially the membrane type-1 MMP (MT1-MMP/MMP14), promote cell motility by proteolysis of extracellular matrix proteins, cell surface receptors and other signaling molecules. It is also well established that the Wnt/planar cell polarity (Wnt/PCP) pathway controls the orientation of cells in a tissue plane in such a way that all cells are oriented in the same front/back direction. We identified a link between these two regulators of cell motility: The proteolysis of protein tyrosine kinase 7 (PTK7), a PCP pseudokinase, by MT1-MMP. We demonstrated that the PTK7 proteolysis by MT1-MMP controls cell migration in early embryogenesis and regulates cancer cell directional motility and invasion. The full-length PTK7 is one of the major cell surface proteins expressed in normal breast epithelial cells and is a major cleavage target of MT1-MMP. The full-length PTK7 efficiently inhibits cell invasion and down-regulates the myosin light chain (MLC) phosphorylation, a downstream event in the Wnt/PCP pathway. MT1-MMP proteolysis of PTK7 reverses the inhibitory signal of the full-length PTK7 and this proteolytic event promotes cell invasion. Thus, PTK7 proteolysis by MT1-MMP is a proteolytic master switch that turns on the motility of cells. This ubiquitous mechanism is conserved in models as diverse as zebrafish embryogenesis and cancer cell invasion. It is likely that aberrations in the PTK7 signaling are detrimental to cell movements. Because both the pro-invasive MT1-MMP and the polarity regulating PTK7 are linked to embryogenesis and cancer, the precise understanding of the downstream signaling events of PTK7 proteolysis will result in a more comprehensive understanding of polarized collective cell motility in development and cancer.
About Vladislav Golubkov
Dr. Golubkov received his PhD from the Laboratory of Cytotechnology at the Institute of Theoretical and Experimental Biophysics, Russian Academy of Science. As a PhD student he developed novel approach to produce snake venom proteins for biotechnology applications by utilizing the snake secretory epithelial cell culture. After graduation from the PhD program in 1999, he moved to the United States to join Dr. Yanina Rozenbeg-Adler’s Targeted Artificial Gene Delivery (TAGD) group at the University of Southern California, Los Angeles (USC) to study the retargeting of gene therapy vectors by biophysical and chemical surface modifications. Later, in 2001, Dr. Golubkov joined Francis Markland’s laboratory at USC and studied the anti-tumor and anti-angiogenic properties of the snake venom disintegrin, contortrostatin. Dr. Golubkov continued to explore the molecular mechanisms of diseases in Dr. Alex Strongin’s laboratory at the Sanford-Burnham Medical Research Institute (2003-present) where he studies matrix metalloproteinases (MMPs) and other proteases in pathology, primarily in cancer.
2011-present, Research Assistant Professor, Sanford-Burnham Medical Research Institute (La Jolla, California).
2007-2011, Staff Scientist, Sanford-Burnham Medical Research Institute (La Jolla, California).
2003-2007, Postdoctoral associate, Sanford-Burnham Medical Research Institute (La Jolla, California).
2000-2003, Postdoctoral associate, Keck School of Medicine, University of Southern California (USC, Los Angeles, California).
1996-1999, Ph.D. (Cell Biology, Biophysics, 1999), Institute of Theoretical and Experimental Biophysics, Laboratory of Cytotechnology, Russian Academy of Science (Russia).