p38γ Mitogen-activated Protein Kinase Signals through Phosphorylating Its Phosphatase PTPH1 in Regulating Ras Protein Oncogenesis and Stress Response

Hou, Songwang; Suresh, Padmanaban S.; Qi, Xiaomei; Lepp, Adrienne; Mirza, Shama P.; Chen, Guan

doi:10.1074/jbc.m111.335794

Cited by 27 publications

(66 citation statements)

References 50 publications

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“…(B, C) Flag immune-precipitates were separated by SDS-PAGE and samples from the numbered region (1-6) were digested, which were then subjected to proteomic analysis as described [22]. MS/MS spectra of heat shock protein 90α peptide HLEINPDHSIIETLR and 90β peptide ADLINNLGTIAK with representative peak matches for b and y ions {detected from the sample 1 but not sample 4 of B}.…”

Section: Resultsmentioning

confidence: 99%

Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer

Xie

Hou

et al. 2014

Oncotarget

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A cancer phenotype is driven by several proteins and targeting a cluster of functionally interdependent molecules should be more effective for therapeutic intervention. This is specifically important for Ras-dependent cancer, as mutated (MT) Ras is non-druggable and targeting its interaction with effectors may be essential for therapeutic intervention. Here, we report that a protein-complex activated by the Ras effector p38γ MAPK is a novel therapeutic target for K-Ras-dependent colon cancer. Unbiased proteomic screening and immune-precipitation analyses identified p38γ interaction with heat shock protein 90 (Hsp90) and K-Ras in K-Ras MT, but not wild-type (WT), colon cancer cells, indicating a role of this complex in Ras-dependent growth. Further experiments showed that this complex requires p38γ and Hsp90 activity to maintain MT, but not WT, K-Ras protein expression. Additional studies demonstrated that this complex is activated by p38γ-induced Hsp90 phosphorylation at S595, which is important for MT K-Ras stability and for K-Ras dependent growth. Of most important, pharmacologically inhibition of Hsp90 or p38γ activity disrupts the complex, decreases K-Ras expression, and selectively inhibits the growth of K-Ras MT colon cancer in vitro and in vivo. These results demonstrated that the p38γ-activated ternary complex is a novel therapeutic target for K-Ras-dependent colon cancer.

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Section: Resultsmentioning

confidence: 99%

Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer

Xie

Hou

et al. 2014

Oncotarget

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“…Tonks (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY; refs. 18, 23) and used previously in our laboratory (20)(21)(22). The pLenti6/Block-iT system (Block-itTM U6 RNAi entry vector Kit, Cat: K4944-00 and Block-itTM Lentiviral RNAi expression system, Cat: K4943-00; Invitrogen) was used to clone sequences for short hairpin RNAs (shRNA).…”

Section: Methodsmentioning

confidence: 99%

“…The pLenti6/Block-iT system (Block-itTM U6 RNAi entry vector Kit, Cat: K4944-00 and Block-itTM Lentiviral RNAi expression system, Cat: K4943-00; Invitrogen) was used to clone sequences for short hairpin RNAs (shRNA). The details of the target sequences used for luciferase and PTPH1 (shLuc and shPTPH1) are described earlier (20)(21)(22). Antibody against PTPH1 (mouse) was kindly provided by Dr. N.K.…”

Section: Methodsmentioning

confidence: 99%

“…Previous genetic analysis showed that PTPH1 and its several family members are mutated in human colon cancer but the functional consequence of these mutations remains unestablished (19). Our recent studies showed that PTPH1 dephosphorylates and cooperates with p38g MAPK to promote Ras oncogenesis through a complex formation (20,21). Importantly, PTPH1 is overexpressed in breast cancer and stimulates breast cancer growth in vitro through collaboration with vitamin D receptor (22).…”

Section: Introductionmentioning

confidence: 97%

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Protein-Tyrosine Phosphatase H1 Increases Breast Cancer Sensitivity to Antiestrogens by Dephosphorylating Estrogen Receptor at Tyr537

Suresh

Migliaccio

et al. 2014

Molecular Cancer Therapeutics

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Estrogen receptor a (ERa or ER) is the only target of breast cancer therapy using antiestrogens. However, about 50% of ER-expressing breast cancer is intrinsically refractory to the antihormone therapy and strategies to improve the therapeutic response are urgently needed. Dynamic ER phosphorylation and dephosphorylation play an important role in ER activity and antihormone response. Although more than 10 kinases participate in phosphorylating ER protein, phosphatases involved remain mostly unidentified. Here, we tested the hypothesis that the protein-tyrosine phosphatase H1 (PTPH1) may regulate ER tyrosine phosphorylation and thereby impact breast cancer antihormone sensitivity. Our results showed that PTPH1 dephosphorylates ER at Tyr537 in vitro and in breast cancer cells. Moreover, PTPH1 stimulates ER nuclear accumulation and increases breast cancer sensitivity to tamoxifen (TAM) and/or fulvestrant in cell culture and in a xenograft model. Further analysis revealed that PTPH1 depends on its catalytic activity to stimulate ER nuclear accumulation and to enhance breast cancer antihormone sensitivity. These studies thus identified PTPH1 as a novel ER phosphatase and further demonstrate a therapeutic potential of enhancing breast cancer sensitivity to antiestrogens through dephosphorylating ER by PTPH1. Mol Cancer Ther; 13(1); 230-8. Ó2013 AACR.

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“…Lyp (subtype NT4, 38% PTP-domain identity with PTP1B), has been shown to be a negative regulator of T-cell activation, and gain-of-function Lyp mutations have been associated with several autoimmune diseases [20–21]. PTPH1 (subtype NT5, 36% PTP-domain identity with PTP1B) acts on the mitogen-activated protein kinase p38γ and has been found to be mutated in human colorectal cancers [22–23]. And, PTPα (subtype R4, 36% PTP-domain identity with PTP1B) is a receptor PTP that dephosphorylates and activates Src-family kinases, thereby regulating a variety of downstream pathways [24].…”

Section: Resultsmentioning

confidence: 99%

A general assay for monitoring the activities of protein tyrosine phosphatases in living eukaryotic cells

Harris¹,

Frumm²,

Bishop³

2013

Analytical Biochemistry

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Protein tyrosine phosphatases (PTPs) are key signal-transduction regulators and have emerged as potential drug targets for inhibitor design. Here we report a yeast-based assay that provides a general means of assessing the activity and/or inhibition of essentially any classical PTP in living cells. The assay uses the activity of an exogenously expressed PTP to counter the activity of a co-expressed and toxic tyrosine kinase, such that only active PTPs are capable of rescuing growth. PTP activity gives rise to both increased growth and decreased phosphotyrosine levels; cellular PTP activity can therefore be monitored by either yeast-growth curves or anti-phosphotyrosine western blots. We show that four PTPs (TCPTP, Shp2, PEST, PTPα) are capable of rescuing the effects of v-Src toxicity. Since these PTPs are chosen from four distinct sub-families, it is likely that biologically and medicinally important PTPs from other subfamilies can similarly function in the cellular PTP assay. Because many small-molecule PTP inhibitors fail to penetrate cell membranes effectively, this cell-based assay has the potential to serve as a useful screening tool for determining the cellular efficacy of candidate inhibitors in a more biologically relevant context than can be provided by an in vitro PTP assay.

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p38γ Mitogen-activated Protein Kinase Signals through Phosphorylating Its Phosphatase PTPH1 in Regulating Ras Protein Oncogenesis and Stress Response

Cited by 27 publications

References 50 publications

Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer

Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer

Protein-Tyrosine Phosphatase H1 Increases Breast Cancer Sensitivity to Antiestrogens by Dephosphorylating Estrogen Receptor at Tyr537

A general assay for monitoring the activities of protein tyrosine phosphatases in living eukaryotic cells

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