PTPN2 regulates the activation of KRAS and plays a critical role in proliferation and survival of KRAS-driven cancer cells

Abstract

RAS genes are the most commonly mutated in human cancers and play critical roles in tumor initiation, progression, and drug resistance. Identification of targets that block RAS signaling is pivotal to develop therapies for RAS-related cancer. As RAS translocation to the plasma membrane (PM) is essential for its effective signal transduction, we devised a high-content screening assay to search for genes regulating KRAS membrane association. We found that the tyrosine phosphatase PTPN2 regulates the plasma membrane localization of KRAS. Knockdown of PTPN2 reduced the proliferation and promoted apoptosis in KRAS-dependent cancer cells, but not in KRAS-independent cells. Mechanistically, PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling. Consistently, analysis of the TCGA database demonstrates that high expression of PTPN2 is significantly associated with poor prognosis of patients with KRAS-mutant pancreatic adenocarcinoma. These results indicate that PTPN2 is a key regulator of KRAS and may serve as a new target for therapy of KRAS-driven cancer. RAS genes are the most commonly mutated in human cancers and play critical roles in tumor initiation, progression, and drug resistance. Identification of targets that block RAS signaling is pivotal to develop therapies for RAS-related cancer. As RAS translocation to the plasma membrane (PM) is essential for its effective signal transduction, we devised a high-content screening assay to search for genes regulating KRAS membrane association. We found that the tyrosine phosphatase PTPN2 regulates the plasma membrane localization of KRAS. Knockdown of PTPN2 reduced the proliferation and promoted apoptosis in KRAS-dependent cancer cells, but not in KRAS-independent cells. Mechanistically, PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling. Consistently, analysis of the TCGA database demonstrates that high expression of PTPN2 is significantly associated with poor prognosis of patients with KRAS-mutant pancreatic adenocarcinoma. These results indicate that PTPN2 is a key regulator of KRAS and may serve as a new target for therapy of KRAS-driven cancer. RAS proteins are small GTPases that regulate diverse cellular processes, including proliferation, differentiation, migration, apoptosis, and senescence (1Malumbres M. Barbacid M. RAS oncogenes: the first 30 years.Nat. Rev. Cancer. 2003; 3 (12778136): 459-46510.1038/nrc1097Crossref PubMed Scopus (1385) Google Scholar). Mammalian cells mainly express three RAS genes that encode four highly homologous proteins: HRAS, NRAS, KRAS4A, and KRAS4B. KRAS4A and KRAS4B result from an alternative splicing at the C terminus of the KRAS gene (2Cox A.D. Fesik S.W. Kimmelman A.C. Luo J. Der C.J. Drugging the undruggable RAS: Mission possible?.Nat. Rev. Drug Discov. 2014; 13 (25323927): 828-85110.1038/nrd4389Crossref PubMed Scopus (1086) Google Scholar). Because KRAS4B is the predominant splice variant of KRAS, it is referred to as KRAS hereafter. RAS genes are the most frequently mutated oncogene in cancer, nearly 20-30% of human malignancies carry RAS gene mutations. Among the RAS gene family, KRAS is the most commonly mutated, which occurs in 71% of pancreatic, 29% of colorectal, and 18.6% of lung carcinomas (3Li S. Balmain A. Counter C.M. A model for RAS mutation patterns in cancers: finding the sweet spot.Nat. Rev. Cancer. 2018; 18 (30420765): 767-77710.1038/s41568-018-0076-6Crossref PubMed Scopus (145) Google Scholar). It has been shown that mutated KRAS not only plays pivotal roles in cancer initiation (4Jackson E.L. Willis N. 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Carver J.O. Zuber J. Luo J. McCormick F. Lowe S.W. Development of siRNA payloads to target KRAS-mutant cancer.Cancer Discov. 2014; 4 (25100204): 1182-119710.1158/2159-8290.CD-13-0900Crossref PubMed Scopus (77) Google Scholar, 11Kamerkar S. LeBleu V.S. Sugimoto H. Yang S. Ruivo C.F. Melo S.A. Lee J.J. Kalluri R. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer.Nature. 2017; 546 (28607485): 498-50310.1038/nature22341Crossref PubMed Scopus (1103) Google Scholar). These observations prompted many groups to target either mutant KRAS directly or downstream effectors. Thus far, directly targeting oncogenic KRAS only succeeded in one certain form, KRASG12C (12Patricelli M.P. Janes M.R. Li L.S. Hansen R. Peters U. Kessler L.V. Chen Y. Kucharski J.M. Feng J. Ely T. Chen J.H. Firdaus S.J. Babbar A. Ren P. Liu Y. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state.Cancer Discov. 2016; 6 (26739882): 316-32910.1158/2159-8290.CD-15-1105Crossref PubMed Scopus (403) Google Scholar, 13Janes M.R. Zhang J. Li L.S. Hansen R. Peters U. Guo X. Chen Y. Babbar A. Firdaus S.J. Darjania L. Feng J. Chen J.H. Li S. Li S. Long Y.O. Thach C. Liu Y. Zarieh A. Ely T. Kucharski J.M. Kessler L.V. Wu T. Yu K. Wang Y. Yao Y. Deng X. Zarrinkar P.P. Brehmer D. Dhanak D. Lorenzi M.V. Hu-Lowe D. Patricelli M.P. Ren P. Liu Y. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor.Cell. 2018; 172 (29373830): 578-589.e1710.1016/j.cell.2018.01.006Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar), which comprises only 12% of KRAS mutations in all human cancers, so it is still needed to develop new target molecules for other oncogenic KRAS. Inhibiting protein–protein interactions and KRAS localization are novel approaches to target mutant KRAS and block oncogenic KRAS signaling (14Fehrenbacher N. Tojal da Silva I. Ramirez C. Zhou Y. Cho K.J. Kuchay S. Shi J. Thomas S. Pagano M. Hancock J.F. Bar-Sagi D. Philips M.R. The G protein-coupled receptor GPR31 promotes membrane association of KRAS.J. Cell Biol. 2017; 216 (28619714): 2329-233810.1083/jcb.201609096Crossref PubMed Scopus (16) Google Scholar, 15Adhikari H. Counter C.M. Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability.Nat. Commun. 2018; 9 (30194290)364610.1038/s41467-018-05692-6Crossref PubMed Scopus (38) Google Scholar, 16Kovalski J.R. Bhaduri A. Zehnder A.M. Neela P.H. Che Y. Wozniak G.G. Khavari P.A. The functional proximal proteome of oncogenic Ras includes mTORC2.Mol. Cell. 2019; 73 (30639242): 830-844.e1210.1016/j.molcel.2018.12.001Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar), although the efficacy in clinical is still unknown. Targeting the KRAS effector signaling pathways could also prove efficacious in treating tumors with KRAS mutations, as the inhibitors have entered clinical trials demonstrating promising clinical activity in KRAS mutant tumor (17Temraz S. Mukherji D. Shamseddine A. Dual inhibition of MEK and PI3K pathway in KRAS and BRAF mutated colorectal cancers.Int. J. Mol. Sci. 2015; 16 (26404261): 22976-2298810.3390/ijms160922976Crossref PubMed Scopus (73) Google Scholar, 18Kinsey C.G. Camolotto S.A. Boespflug A.M. Guillen K.P. Foth M. Truong A. Schuman S.S. Shea J.E. Seipp M.T. Yap J.T. Burrell L.D. Lum D.H. Whisenant J.R. Gilcrease 3rd, G.W. Cavalieri C.C. Rehbein K.M. Cutler S.L. Affolter K.E. Welm A.L. Welm B.E. Scaife C.L. Snyder E.L. McMahon M. 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Full Text Full Text PDF PubMed Scopus Google Scholar). targeting and in have been to M.T. S.J. C.J. A.M. Liu D. E. S.L. of and in Res. 2001; Google Scholar). the clinical of inhibition of interactions an therapeutic to the KRAS oncogenic activity (14Fehrenbacher N. Tojal da Silva I. Ramirez C. Zhou Y. Cho K.J. Kuchay S. Shi J. Thomas S. Pagano M. Hancock J.F. Bar-Sagi D. Philips M.R. The G protein-coupled receptor GPR31 promotes membrane association of KRAS.J. Cell Biol. 2017; 216 (28619714): 2329-233810.1083/jcb.201609096Crossref PubMed Scopus (16) Google Scholar, N. S. C. R. S. S. M. B. M. D. G.W. L. H. inhibition of affects Ras localization and Biol. 6 PubMed Scopus Google Scholar, A. V. D. L. F. S.A. C. M. A. The the and of Ras Cell Biol. 2011; PubMed Scopus Google Scholar, G. B. S. N. A. M. S.A. G. A. H. inhibition of the oncogenic KRAS PubMed Scopus Google Scholar, M. N. B. M. L. to the plasma membrane of and 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). we devised a high-content screening assay and an siRNA screening to key molecules for oncogenic KRAS plasma membrane association. We for the first phosphatase regulates the KRAS plasma membrane association and plays an in KRAS-dependent cancer proliferation and that PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling. that PTPN2 could serve as a therapeutic target for KRAS-driven cancer. genes for KRAS membrane we an screening assay that the of membrane association we a human We found that the of proteins are to the We a with targets that regulate protein using an genes and in The siRNA as a cells with for in one PTPN2 significantly the of We PTPN2 as as KRAS from to the screening different PTPN2 and PTPN2 could the of PTPN2 in cells We the of the using a membrane protein and found that silencing PTPN2 reduced the translocation of to the with the and the of in the and These that PTPN2 plays an in regulating the plasma membrane association of We next the of PTPN2 cancer using to PTPN2 in a of mutant human cancer and and KRAS human cancer and to KRAS as a with for the As shown in silencing PTPN2 with the proliferation of and cells, and but significantly inhibition of and it is not the in cells. the of PTPN2 with that of KRAS that PTPN2 plays a critical in KRAS oncogenic signaling. which is to the of either PTPN2 or KRAS the expression of PTPN2 and KRAS in all We the of PTPN2 the three mutant KRAS-dependent using different found to the expression of PTPN2 and the proliferation of the C and of proliferation, we the of PTPN2 and KRAS proliferation a with the results of the of cells significantly in all for It is that the of PTPN2 is that of KRAS in and that PTPN2 has activity the proliferation signaling of KRAS in cells. We also the of PTPN2 tumor with KRAS, or for with and analysis that the of apoptosis in KRAS-dependent tumor significantly that of The of PTPN2 is that of KRAS in KRAS-dependent tumor that PTPN2 is for the signaling of KRAS. the which PTPN2 regulates the proliferation and of KRAS-dependent tumor cells, we first PTPN2 affects the KRAS using an As shown in the of significantly in cells with PTPN2 either or different with that in cells with the of KRAS in cells also treating with PTPN2 We next PTPN2 affects the activation of KRAS downstream signaling As shown in both KRAS and PTPN2 could the phosphorylation of MEK and in KRAS-dependent tumor and that PTPN2 is for the activation of oncogenic KRAS and its downstream signaling We also the protein of in cells in the of protein As shown in the KRAS protein to PTPN2 only a for the The different of PTPN2 the and KRAS may the KRAS is the mutant form, the KRAS is the We also the of PTPN2 of the KRAS protein in the KRAS mutant We cancer cells mutant with either or PTPN2 As shown in C and mutant KRAS in PTPN2 cells. that PTPN2 is not in mutant KRAS protein It has been shown that tyrosine phosphorylation of KRAS its signal KRAS Y. T. N. J. I. J. B. Lee J.E. J.J. Zhang M. M. phosphorylation of KRAS of and Commun. 2019; PubMed Scopus Google Scholar). PTPN2 is a of the and has been shown to several tyrosine We PTPN2 regulates KRAS signaling KRAS. with We found the of KRAS in cells significantly of PTPN2 A and These results indicate PTPN2 is also a tyrosine phosphatase for KRAS. that the KRAS phosphorylation to PTPN2 we PTPN2 isoforms and and a mutant to for of and PTPN2 siRNA cells PTPN2 expression of but not the of tyrosine phosphorylation of KRAS C and result that PTPN2 regulates tyrosine phosphorylation of KRAS its tyrosine phosphatase activity and that is the to carry that PTPN2 plays an in the of KRAS-dependent tumor cells. the of PTPN2 expression in cancers, we clinical We KRAS KRAS PTPN2 and clinical of cancers from TCGA We first analysis to the of patients mutant or KRAS in pancreatic lung and colorectal As shown in KRAS mutation is associated with poor prognosis of but not that of or We the of PTPN2 of patients KRAS mutations. As shown in high expression of PTPN2 is significantly associated with poor prognosis in KRAS-mutant patients but not in patients with or the high expression of KRAS is significantly associated with poor prognosis in and but not in PTPN2 expression are not significantly associated with in KRAS high expression patients or KRAS expression patients with and and These clinical that PTPN2 plays an in It has been that 20-30% human cancers, including a high of pancreatic, and colorectal cancers, are mutations in KRAS. have shown that mutation could the progression of the human cancer, and a mutated of is to pancreatic and lung cancer C. N. A. P. M. M. V. Barbacid M. an K-ras oncogene is highly cellular Cell. 2003; 4 Full Text Full Text PDF PubMed Scopus Google Scholar, A. V. C. S. Y. D. Jacks T. C.V. A.M. Tuveson D.A. and pancreatic cancer and its early in the Cell. 2003; 4 Full Text Full Text PDF PubMed Scopus Google Scholar). silencing with siRNA in significantly the of (9Pecot C.V. Wu S.Y. Bellister S. Filant J. Rupaimoole R. Hisamatsu T. Bhattacharya R. Maharaj A. Azam S. Rodriguez-Aguayo C. Nagaraja A.S. Morelli M.P. Gharpure K.M. Waugh T.A. Gonzalez-Villasana V. Zand B. Dalton H.J. Kopetz S. Lopez-Berestein G. Ellis L.M. Sood A.K. Therapeutic silencing of KRAS using systemically delivered siRNAs.Mol. Cancer Ther. 2014; 13 (25281617): 2876-288510.1158/1535-7163.MCT-14-0074Crossref PubMed Scopus (61) Google Scholar, 10Yuan T.L. Fellmann C. Lee C.S. Ritchie C.D. Thapar V. Lee L.C. Hsu D.J. Grace D. Carver J.O. Zuber J. Luo J. McCormick F. Lowe S.W. Development of siRNA payloads to target KRAS-mutant cancer.Cancer Discov. 2014; 4 (25100204): 1182-119710.1158/2159-8290.CD-13-0900Crossref PubMed Scopus (77) Google Scholar, 11Kamerkar S. LeBleu V.S. Sugimoto H. Yang S. Ruivo C.F. Melo S.A. Lee J.J. Kalluri R. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer.Nature. 2017; 546 (28607485): 498-50310.1038/nature22341Crossref PubMed Scopus (1103) Google Scholar). have in the 3 the KRAS signaling drug in KRAS has been the that KRAS regulates signaling pathways for only associated with the (14Fehrenbacher N. Tojal da Silva I. Ramirez C. Zhou Y. Cho K.J. Kuchay S. Shi J. Thomas S. Pagano M. Hancock J.F. Bar-Sagi D. Philips M.R. The G protein-coupled receptor GPR31 promotes membrane association of KRAS.J. Cell Biol. 2017; 216 (28619714): 2329-233810.1083/jcb.201609096Crossref PubMed Scopus (16) Google Scholar, J.F. Ras proteins: different from different Rev. Mol. Cell Biol. 2003; 4 PubMed Scopus Google Scholar, J.F. Ras plasma membrane J. PubMed Scopus Google Scholar, M. J. Zhang J. C. B. Ren R. its plasma membrane Cancer Ther. 2017; 16 PubMed Scopus Google Scholar), targeting KRAS membrane translocation has an alternative we a siRNA using an high-content We found that PTPN2 is for the effective localization of KRAS, and PTPN2 is for to a Mechanistically, KRAS analysis of the from we found that high PTPN2 expression is associated with poor prognosis of KRAS-mutant also as phosphatase is a phosphatase that is H. from a human a of the Sci. PubMed Scopus Google Scholar), and plays critical roles in and E. H. C. A. D. N. M. K. B. M. A. U. A. V. A. T. T. M. of in PTPN2 and Commun. 2015; 6 PubMed Scopus Google Scholar, F. T. A. T. PTPN2 regulates and 2017; PubMed Scopus Google Scholar, F. F. Yu D. T. and and promotes the of 2017; PubMed Scopus Google Scholar). The of PTPN2 in tumors has to in It has been that PTPN2 is frequently mutated and in and that PTPN2 negatively regulates the signaling M. I. T. K. N. C. K. F. T. I. P. J. J. of the protein tyrosine phosphatase gene PTPN2 in PubMed Scopus Google Scholar). have found that PTPN2 as an PTPN2 in and proliferation and the cancer in vivo A. Y. is for the of PubMed Scopus Google Scholar). It also shown that PTPN2 expression are associated with prognosis in patients with and with a high expression of PTPN2 to have a poor that PTPN2 tumor Zhang Li Liu X. J.H. T. Li S.W. and clinical of PTPN2 expression from of 2018; 15 PubMed Scopus Google Scholar). we for the first that PTPN2 plays a in KRAS-driven cancer. It has been that KRAS is which the of and the to KRAS and the to which the of promotes of KRAS and signaling Y. T. N. J. I. J. B. Lee J.E. J.J. Zhang M. M. phosphorylation of KRAS of and Commun. 2019; PubMed Scopus Google Scholar). PTPN2 is as phosphatase that KRAS and regulates the activation of KRAS and its downstream signaling. It has been that the of mutations in KRAS may have an its to and the drug of cancer for has shown a the cancer mutations in KRAS at but not and F. C. C.J. G. D. C. K. A. J. T. A. V. C. C.M. Wang G. A.L. M. RAS the phosphatase of mutant and Cell Biol. 2018; PubMed Scopus Google Scholar). we found it is that the of PTPN2 for KRAS activation is of the mutant KRAS which and PTPN2 and KRAS, but signal molecules are The to have shown that cancers with reduced cells as as reduced of cells the cells, which tumor to therapy X. D. P. Li J. Wang G. Li J. M. S. X. Chen P. R. K. D. A. D.J. Zhang J. Kopetz S. Wang R.A. and therapy in colorectal cancer.Cancer Cell. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar). is that cancers could the and which are in therapy in patients with cancer X. D. P. Li J. Wang G. Li J. M. S. X. Chen P. R. K. D. A. D.J. Zhang J. Kopetz S. Wang R.A. and therapy in colorectal cancer.Cancer Cell. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar). It is that of results in an in and activation of cells, and of M. P. tyrosine phosphatase regulates signaling in PubMed Scopus (60) Google Scholar, R.T. K. S.A. J. D. E. vivo screening identifies as a cancer 2017; PubMed Scopus Google Scholar). has been as a novel cancer target in a screening in of gene the efficacy of therapy in R.T. K. S.A. J. D. E. vivo screening identifies as a cancer 2017; PubMed Scopus Google Scholar). Moreover, one has that of promotes in from colorectal cancer M.R. R. L. C. S. K. A. F. M. G. M. PTPN2 regulates activation and onset of and 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). inhibition of PTPN2 could KRAS cancer, tumor we PTPN2 is a key regulator of KRAS activation and signaling The results indicate that PTPN2 may a novel therapeutic target for KRAS-driven lung and pancreatic and and cancer and the from the and and using These cells to cells. and cells in and cells in and in essential with and the cells in a at PTPN2 and inactive mutation as C. Subrahmanyam R. Ren R. Oncogenic NRAS, KRAS, and HRAS exhibit different leukemogenic potentials in mice.Cancer Res. 2007; 67 (17671181): 7139-714610.1158/0008-5472.CAN-07-0778Crossref PubMed Scopus (67) Google Scholar, H. Liu P. Zhang R. Wu M. Li D. X. Zhang C. B. Chen B. Chen Ren R. of and the in oncogenic 2015; PubMed Scopus Google Scholar). cells in with at of using the cells a and a one for with and in a The for siRNA screening in cells using a siRNA at in silencing for using with using an for with a using the The siRNA in cells with and in with and from the and with the and from Cell and from from and from The or The with an shown is a of a of The assay to the of the with siRNA using at a of and in for and for 3 cells three with and and the cells with Cell with for and with for with for at cells with for 30 at cells with for 15 The of cells and using the and using the with siRNA for cells and with and in cells with and for 15 at in the and using a with the with siRNA using or at a of and in for or apoptosis and for cells for analysis as and for the Cell as The from and the for KRAS siRNA and PTPN2 siRNA are as and KRAS and KRAS and KRAS and PTPN2 and and PTPN2 and Cell using the Cell as N. Yu Y. Wu M. Zhang R. Zhang T. C. L. Zhang J. Deng X. Chen Ren R. A novel in Res. 2018; Google Scholar). and cells with siRNA using or at a of and in at a of to using the The using an KRAS activity using RAS activation assay to the with cells in with and phosphatase inhibitors and with of for at 4 the three with the activated KRAS to the of to analysis as and using an cells with siRNA using at a of and in at a of cells the using the the and for in with and phosphatase inhibitors and with of or for at 4 the three with the to the of to analysis as and using an or cells and with siRNA using at a of and in at a of the cells with and in with and to analysis as The KRAS PTPN2 and clinical of cancers from the TCGA with clinical KRAS mutations, KRAS expression and PTPN2 expression The groups the expression of the expression of the gene of using and groups using of are as using to are We and for with plasma membrane phosphatase pancreatic lung colorectal protein human analysis of

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