Missing-in-Metastasis regulates cell motility and invasion via PTPdelta-mediated changes in SRC activity

Chaudhary, F., Lucito, R., Tonks, N. K. (October 2014) Missing-in-Metastasis regulates cell motility and invasion via PTPdelta-mediated changes in SRC activity. Biochemical Journal, 465 (1). pp. 89-101. ISSN 0264-6021

URL: http://www.ncbi.nlm.nih.gov/pubmed/25287652
DOI: 10.1042/bj20140573

Abstract

Missing in Metastasis (MIM), also known as MTSS1, is a scaffold protein that is down-regulated in multiple metastatic cancer cell lines compared to non-metastatic counterparts. MIM regulates cytoskeletal dynamics and actin polymerization, and has been implicated in the control of cell motility and invasion. MIM has also been shown to bind to a receptor PTP, PTPdelta, an interaction that may provide a link between tyrosine phosphorylation-dependent signaling and metastasis. We used shRNA-mediated gene silencing to investigate the consequences of loss of MIM on the migration and invasion of the MCF10A mammary epithelial cell model of breast cancer. We observed that suppression of MIM by RNAi enhanced migration and invasion of MCF10A cells, effects that were associated with increased levels of PTPdelta. Furthermore, analysis of human clinical data indicated that PTPdelta was elevated in breast cancer samples when compared to normal tissue. We demonstrated that the SRC protein tyrosine kinase is a direct substrate of PTPdelta and, upon suppression of MIM, we observed changes in the phosphorylation status of SRC, in particular the inhibitory site (Tyr 527) was hypophosphorylated, whereas the activating autophosphorylation site (Tyr 416) was hyperphosphorylated. Thus, the absence of MIM led to PTPdelta-mediated activation of SRC. Finally, the SRC inhibitor SU6656 counteracted the effects of MIM suppression on cell motility and invasion. This study illustrates that both SRC and PTPdelta have the potential to be therapeutic targets for metastatic tumors associated with loss of MIM.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > breast cancer
diseases & disorders > cancer > metastasis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein tyrosine phosphatase
CSHL Authors:
Communities: CSHL labs > Lucito lab
CSHL labs > Tonks lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: Matt Covey
Date: 7 October 2014
Date Deposited: 06 Jan 2015 17:28
Last Modified: 15 Oct 2015 20:04
PMCID: PMC4312213
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30998

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