Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase*

Fan, Guang; Aleem, Saadat U.; Yang, Ming; Miller, W. Todd; Tonks, Nicholas K.

doi:10.1074/jbc.m115.651703

Cited by 39 publications

(49 citation statements)

References 45 publications

(35 reference statements)

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“…In fact, upon down-regulation, the activation loop of MET is dephosphorylated and inactivated by an ER-anchored protein tyrosine phosphatase, PTP1B. Interestingly, we reported previously that there was a decrease in expression of PTP1B in all 11 tested ovarian cancer cell lines compared with the two normal controls (Fan et al 2013(Fan et al , 2015, further supporting the idea that MET-dependent signals may be augmented at the level of both enhanced phosphorylation and activation as well as attenuated dephosphorylation and inactivation.…”

Section: Discussionsupporting

confidence: 57%

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HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer

et al. 2016

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Ovarian cancer cells disseminate readily within the peritoneal cavity, which promotes metastasis, and are often resistant to chemotherapy. Ovarian cancer patients tend to present with advanced disease, which also limits treatment options; consequently, new therapies are required. The oncoprotein tyrosine kinase MET, which is the receptor for hepatocyte growth factor (HGF), has been implicated in ovarian tumorigenesis and has been the subject of extensive drug development efforts. Here, we report a novel ligand-and autophosphorylation-independent activation of MET through the nonreceptor tyrosine kinase feline sarcoma-related (FER). We demonstrated that the levels of FER were elevated in ovarian cancer cell lines relative to those in immortalized normal surface epithelial cells and that suppression of FER attenuated the motility and invasive properties of these cancer cells. Furthermore, loss of FER impaired the metastasis of ovarian cancer cells in vivo. Mechanistically, we demonstrated that FER phosphorylated a signaling site in MET: Tyr1349. This enhanced activation of RAC1/PAK1 and promoted a kinaseindependent scaffolding function that led to recruitment and phosphorylation of GAB1 and the specific activation of the SHP2-ERK signaling pathway. Overall, this analysis provides new insights into signaling events that underlie metastasis in ovarian cancer cells, consistent with a prometastatic role of FER and highlighting its potential as a novel therapeutic target for metastatic ovarian cancer.

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Section: Discussionsupporting

confidence: 57%

“…Detailed protocols are described in Fan et al (2015). The shRNAs used were FER shRNA#1 seq (5 ′ -GCAGAAAGTTTGC AAGTAATG-3 ′ ) and FER shRNA#2 seq (5 ′ -GCCAAGGAAC GATACGACAAA-3 ′ )siRNAs targeting MET were purchased from Sigma: MET siRNA1 (SASI_Hs01_00133002) and siRNA12 (SASI_WI_00000001).…”

Section: Rnaimentioning

confidence: 99%

HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer

et al. 2016

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“…It is known that sucrose gradient ultracentrifugation can resolve lipid raft and cytosol fractions. As expected, PAG, a marker protein for lipid rafts [20, 21], was detected in the early fractions, whereas the cytosolic proteins BRK and PLCγ1 [22] were both detected in later fractions (Fig 4A). FER and MET, which displayed a similar distribution, were detected in later fractions.…”

Section: Resultssupporting

confidence: 70%

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

Zhang

Zuo

Zhang

et al. 2018

Cellular Signalling

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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.

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“…It is noted that Exon5 encodes residues from 119 to 164 so that the ΔE5 mutant lacks Lys120, implying that this mutant may be somewhat defective in binding specific substrates such as Src. However, recently, Fan et al reported that PTP1B potentiated Src activity indirectly via dephosphorylation of CBP/PAG with concomitant disruption of its association with CSK [21]. The mechanism by which PTP1B activates Src is more complicated than is currently believed, and more studies with PTP1B and the ΔE5 PTP1B mutant isoform are needed to clarify the relationship between PTP1B and Src activation.…”

Section: Discussionmentioning

confidence: 99%

Cell Transformation by PTP1B Truncated Mutants Found in Human Colon and Thyroid Tumors

et al. 2016

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Expression of wild-type protein tyrosine phosphatase (PTP) 1B may act either as a tumor suppressor by dysregulation of protein tyrosine kinases or a tumor promoter through Src dephosphorylation at Y527 in human breast cancer cells. To explore whether mutated PTP1B is involved in human carcinogenesis, we have sequenced PTP1B cDNAs from human tumors and found splice mutations in ~20% of colon and thyroid tumors. The PTP1BΔE6 mutant expressed in these two tumor types and another PTP1BΔE5 mutant expressed in colon tumor were studied in more detail. Although PTP1BΔE6 revealed no phosphatase activity compared with wild-type PTP1B and the PTP1BΔE5 mutant, its expression induced oncogenic transformation of rat fibroblasts without Src activation, indicating that it involved signaling pathways independent of Src. The transformed cells were tumourigenic in nude mice, suggesting that the PTP1BΔE6 affected other molecule(s) in the human tumors. These observations may provide a novel therapeutic target for colon and thyroid cancer.

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Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase*

Cited by 39 publications

References 45 publications

HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer

HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer

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

Cell Transformation by PTP1B Truncated Mutants Found in Human Colon and Thyroid Tumors

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