MFAP3L activation promotes colorectal cancer cell invasion and metastasis.

An abundance of microfibril-associated glycoprotein 3-like (MFAP3L) significantly correlates with distant metastasis in colorectal cancer (CRC), although the mechanism has yet to be explained. In this study, we observed that MFAP3L knock-down resulted in reduced CRC cell invasion and hepatic metastasis. We evaluated the cellular location and biochemical functions of MFAP3L and found that this protein was primarily localized in the nucleus of CRC cells and acted as a protein kinase. When EGFR translocated into the nucleus upon stimulation with EGF, MFAP3L was phosphorylated at Tyr287 within its SH2 motif, and the activated form of MFAP3L phosphorylated ERK2 at Thr185 and Tyr187. Moreover, the metastatic behavior of CRC cells in vitro and in vivo could be partially explained by activation of the nuclear ERK pathway through MFAP3L phosphorylation. Hence, we experimentally demonstrated for the first time that MFAP3L likely participates in the nuclear signaling of EGFR and ERK2 and acts as a novel nuclear kinase that impacts CRC metastasis.

[1]  M. McMahon,et al.  Extracellular Signal-regulated Kinase (ERK)-dependent Gene Expression Contributes to L1 Cell Adhesion Molecule-dependent Motility and Invasion* , 2004, Journal of Biological Chemistry.

[2]  K. Makino,et al.  Nuclear localization of EGF receptor and its potential new role as a transcription factor , 2001, Nature Cell Biology.

[3]  G. Nolan,et al.  The ERK Mitogen-Activated Protein Kinase Pathway Contributes to Ebola Virus Glycoprotein-Induced Cytotoxicity , 2006, Journal of Virology.

[4]  W. Wong,et al.  A gene signature predictive for outcome in advanced ovarian cancer identifies a survival factor: microfibril-associated glycoprotein 2. , 2009, Cancer cell.

[5]  L. Jianmin,et al.  Molecular cloning, identification and characteristics of NYD-SP9: Gene coding protein kinase presumably involved in spermatogenesis , 2002 .

[6]  W. Schiemann,et al.  Microfibril-associate glycoprotein-2 (MAGP-2) promotes angiogenic cell sprouting by blocking notch signaling in endothelial cells. , 2008, Microvascular research.

[7]  A. Wells,et al.  Tumor invasion: role of growth factor-induced cell motility. , 2000, Advances in cancer research.

[8]  C. Rao,et al.  Functional nuclear epidermal growth factor receptors in human choriocarcinoma JEG-3 cells and normal human placenta. , 1995, Endocrinology.

[9]  Sheng-Chieh Hsu,et al.  Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. , 2005, Cancer cell.

[10]  D. Rimm,et al.  Quantitative Determination of Nuclear and Cytoplasmic Epidermal Growth Factor Receptor Expression in Oropharyngeal Squamous Cell Cancer by Using Automated Quantitative Analysis , 2005, Clinical Cancer Research.

[11]  G. Weinmaster,et al.  Microfibrillar Proteins MAGP-1 and MAGP-2 Induce Notch1 Extracellular Domain Dissociation and Receptor Activation* , 2006, Journal of Biological Chemistry.

[12]  Xiu-Yun Tian,et al.  The significance of a group of molecular markers and clinicopathological factors in identifying colorectal liver metastasis. , 2011, Hepato-gastroenterology.

[13]  Rudy Juliano,et al.  Mitogenic signal transduction by integrin- and growth factor receptor-mediated pathways. , 2004, Molecules and cells.

[14]  A. Citri,et al.  EGF–ERBB signalling: towards the systems level , 2006, Nature Reviews Molecular Cell Biology.

[15]  G. Carpenter Nuclear localization and possible functions of receptor tyrosine kinases. , 2003, Current opinion in cell biology.

[16]  K. Iljin,et al.  Differentiation-promoting culture of competent and noncompetent keratinocytes identifies biomarkers for head and neck cancer. , 2012, The American journal of pathology.

[17]  J. Banyard,et al.  A prognostic gene signature in advanced ovarian cancer reveals a microfibril-associated protein (MAGP2) as a promoter of tumor cell survival and angiogenesis , 2010, Cell Adhesion & Migration.

[18]  Siqi Liu,et al.  Evaluation of hepatic-metastasis risk of colorectal cancer upon the protein signature of PI3K/AKT pathway. , 2008, Journal of proteome research.

[19]  J. Pouysségur,et al.  The Dual Specificity Mitogen-activated Protein Kinase Phosphatase-1 and −2 Are Induced by the p42/p44MAPK Cascade* , 1997, The Journal of Biological Chemistry.

[20]  M. Cobb,et al.  Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. , 2001, Endocrine reviews.

[21]  J. Schlessinger,et al.  Nuclear Signaling by Receptor Tyrosine Kinases: The First Robin of Spring , 2006, Cell.

[22]  H. Reber,et al.  Nerve growth factor stimulates MMP-2 expression and activity and increases invasion by human pancreatic cancer cells , 2004, Clinical & Experimental Metastasis.

[23]  J. Haycock Peptide substrates for ERK1/2: structure-function studies of serine 31 in tyrosine hydroxylase , 2002, Journal of Neuroscience Methods.

[24]  M. Hung,et al.  Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer. , 2005, Cancer research.

[25]  G. Haegeman,et al.  Transcriptional activation of the NF‐κB p65 subunit by mitogen‐ and stress‐activated protein kinase‐1 (MSK1) , 2003, The EMBO journal.

[26]  L. Maffei,et al.  Dynamic regulation of ERK2 nuclear translocation and mobility in living cells , 2006, Journal of Cell Science.