Spatial regulation of signaling by the coordinated action of the protein tyrosine kinases MET and FER

Zhang, Jiali, Wang, Zuo, Zhang, Siwei, Chen, Yanxun, Xiong, Xuexue, Li, Xiaojuan, Tonks, Nicholas K., Fan, Gaofeng (June 2018) Spatial regulation of signaling by the coordinated action of the protein tyrosine kinases MET and FER. Cellular Signalling, 50. pp. 100-110. ISSN 0898-6568

URL: https://www.ncbi.nlm.nih.gov/pubmed/29920310
DOI: 10.1016/j.cellsig.2018.06.006

Abstract

A critical aspect of understanding the regulation of signal transduction is not only to identify the protein-protein interactions that govern assembly of signaling pathways, but also to understand how those pathways are regulated in time and space. In this report, we have applied both gain-of-function and loss-of-function analyses to assess the role of the non-receptor protein tyrosine kinase FER in activation of the HGF Receptor protein tyrosine kinase MET. Overexpression of FER led to direct phosphorylation of several signaling sites in MET, including Tyr1349, but not the activation loop residues Tyr1234/5; in contrast, suppression of FER by RNAi revealed that phosphorylation of both a C-terminal signaling site (Tyr1349) and the activation loop (Tyr1234/5) were influenced by the function of this kinase. Adaptin β, a component of the adaptor protein complex 2 (AP-2) that links clathrin to receptors in coated vesicles, was recruited to MET following FER-mediated phosphorylation. Furthermore, we provide evidence to support a role of FER in maintaining plasma membrane distribution of MET and thereby delaying protein-tyrosine phosphatase PTP1B-mediated inactivation of the receptor. Simultaneous up-regulation of FER and down-regulation of PTP1B observed in ovarian carcinoma-derived cell lines would be expected to contribute to persistent activation of HGF-MET signaling, suggesting that targeting of both FER and MET may be an effective strategy for therapeutic intervention in ovarian cancer.

Item Type: Paper
Uncontrolled Keywords: FER MET PTP1B Endocytosis Ovarian cancer
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
diseases & disorders > cancer > cancer types > ovarian cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein tyrosine phosphatase
CSHL Authors:
Communities: CSHL labs > Tonks lab
Depositing User: Matt Covey
Date: 18 June 2018
Date Deposited: 20 Jun 2018 20:32
Last Modified: 23 Jul 2018 16:28
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36750

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