Functions of Shp2 in cancer

Zhang, Jie; Zhang, Fei; Niu, Ruifang

doi:10.1111/jcmm.12618

Cited by 230 publications

(188 citation statements)

References 98 publications

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“…STAT proteins are phosphorylated, thus activated, by members of the tyrosine kinase Janus kinase (JAK) and dephosphorylated by Protein Tyrosine Phosphatase SHP-2 (37). It has been reported that muscle invasive BC tissues are characterized by nuclear expression of phosphorylated STAT3, and JAK2 is responsible for its phosphorylation at Tyr705 in muscle invasive BC cells (36).…”

Section: Resultsmentioning

confidence: 99%

Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145

Jiang

Huang

et al. 2017

Molecular Cancer Therapeutics

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Although miR-145 is the most frequently down-regulated miRNA in bladder cancer (BC), its exact stage-association and downstream effector have not been defined. Here, we found that miR-145 was upregulated in human BC patients with lymph node metastasis and in metastatic T24T cell line. Forced expression of miR-145 promoted anchorage-independent growth of T24T cells accompanied by the down-regulation of forkhead box class O1 (FOXO1). In contrast, in non-metastatic T24 cells, miR-145 overexpression inhibited cell growth with upregulation of FOXO1 and the knockdown of FOXO1 abolished the miR-145-mediated inhibition of cell growth. Mechanistic studies revealed that miR-145 directly bound to and attenuated 3′UTR activity of foxo1 mRNA in both T24 and T24T cells. Interestingly, miR-145 suppressed STAT3 phosphorylation at Tyr705 and increased foxo1 promoter transcriptional activity in T24 cells, but not in T24T cells, suggesting a role of STAT3 in the divergent responses to miR-145. Supporting this was our finding that STAT3 knockdown mimicked miR-145-mediated upregulation of FOXO1 in T24T cells and inhibition of anchorage-independent growth. Consistently, ectopic expression of miR-145 promoted tumor formation of xenograft T24T cells, whereas such promoting effect became inhibitory due to specific knockdown of STAT3. Together, our findings demonstrate the stage-specific association and function of miR-145 in BCs, and provide novel insights into the therapeutic targeting of miR-145.

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Section: Resultsmentioning

confidence: 99%

Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145

Jiang

Huang

et al. 2017

Molecular Cancer Therapeutics

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“…It is a docking protein for the GRB2/SOS complex, thereby promoting MAPK activation and cell division (Figure 1). PTPN11 is frequently altered in Noonan and Leopard syndromes and cancer cells (Zhang et al, 2015). Analyses of the D61G mutation, frequent in RASopathies, showed that it is gain-function-change, activating the proto-oncogene SRC tyrosine kinase, that in turn activates the serine/threonine kinases PLK1 inducing chromosomal instability and disruption of mitosis (Liu et al, 2016).…”

Section: Comparisons Of Specific Genesmentioning

confidence: 99%

RASopathy Gene Mutations in Melanoma

Halaban

Krauthammer

2016

Journal of Investigative Dermatology

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Next-Generation sequencing (NGS) of melanomas has unraveled critical “driver” genes and genomic abnormalities, mostly defined as occurring at high frequency. In addition, less abundant mutations are present that link melanoma to a set of disorders, commonly called RASopathies. These disorders which include neurofibromatosis, Noonan and Legius syndromes, harbor germline mutations in various RAS/MAPK signaling pathway genes. We highlight shared amino acid substitutions between this set of RASopathy mutations and those observed in large-scale melanoma sequencing data, uncovering a significant overlap. We review the evidence that these mutations activate the MAPK pathway in melanoma, and are involved in melanomagenesis. Furthermore, we discuss the observations that two or more RASopathy mutations often co-occur in melanoma, and may act synergistically on activating the pathway.

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“…SHP2 is a non-receptor tyrosine phosphatase that is ubiquitously expressed in vertebrate cells and tissues [19]. SHP2 possesses two SH2 domains, termed N-SH2 and C-SH2, and a protein tyrosine phosphatase (PTP) domain.…”

Section: Introductionmentioning

confidence: 99%

Targeting endogenous proteins for degradation through the affinity-directed protein missile system

et al. 2017

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Targeted proteolysis of endogenous proteins is desirable as a research toolkit and in therapeutics. CRISPR/Cas9-mediated gene knockouts are irreversible and often not feasible for many genes. Similarly, RNA interference approaches necessitate prolonged treatments, can lead to incomplete knockdowns and are often associated with off-target effects. Targeted proteolysis can overcome these limitations. In this report, we describe an affinity-directed protein missile (AdPROM) system that harbours the von Hippel–Lindau (VHL) protein, the substrate receptor of the Cullin2 (CUL2) E3 ligase complex, tethered to polypeptide binders that selectively bind and recruit endogenous target proteins to the CUL2-E3 ligase complex for ubiquitination and proteasomal degradation. By using synthetic monobodies that selectively bind the protein tyrosine phosphatase SHP2 and a camelid-derived VHH nanobody that selectively binds the human ASC protein, we demonstrate highly efficient AdPROM-mediated degradation of endogenous SHP2 and ASC in human cell lines. We show that AdPROM-mediated loss of SHP2 in cells impacts SHP2 biology. This study demonstrates for the first time that small polypeptide binders that selectively recognize endogenous target proteins can be exploited for AdPROM-mediated destruction of the target proteins.

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Functions of Shp2 in cancer

Cited by 230 publications

References 98 publications

Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145

Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145

RASopathy Gene Mutations in Melanoma

Targeting endogenous proteins for degradation through the affinity-directed protein missile system

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