PTP1B Contributes to the Oncogenic Properties of Colon Cancer Cells through Src Activation

Zhu, Shudong; Bjorge, Jeffrey D.; Fujita, Daishi

doi:10.1158/0008-5472.can-06-4338

Cited by 147 publications

(129 citation statements)

References 45 publications

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“…We found that the specific activity of Src kinase (activity per molecule) was greatly increased in all seven of the colon cancer cell lines tested, including SW48, DLD-1, HCT 116, HT-29, Caco-2, COLO 201 and LS 174T, as compared to the normal colon cell lines FHC and CCD18Co, ranging from 5.2-to 18.7-fold (Zhu et al, 2007), indicating that Src is activated in these cancer cell lines.…”

Section: Resultsmentioning

confidence: 89%

“…In breast cancer, colon cancer and pancreatic cancer, Src kinase activity has been found to be elevated (reviewed in Irby and Yeatman, 2000). Downregulating Src activity with antisense RNA in the colon cancer cell line HT-29 (Staley et al, 1997) or with siRNA in the colon cancer cell line SW48 (Zhu et al, 2007) reduces colony formation numbers in soft agar, demonstrating that elevated Src activity plays an important role in colon cancer tumorigenicity.…”

Section: Introductionmentioning

confidence: 99%

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Decreased CHK protein levels are associated with Src activation in colon cancer cells

et al. 2007

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Src activation has been associated with colon cancers but the mechanism underlying Src activation is largely unknown. Csk-homologous kinase (CHK) can inhibit the kinase activity of certain Src kinase family members in vitro by phosphorylating the C-terminal tyrosine and by a non-catalytic mechanism. CHK was previously reported to be expressed primarily in brain and hematopoietic cells. We report herein that CHK is also expressed in normal colon cell lines. Furthermore, CHK protein levels are significantly decreased in various colon cancer cell lines and the decrease correlates with the increased specific activity of Src in these cell lines, while the level of the other Src inhibitory kinase, C-terminal Src kinase, is not significantly changed. CHK is also expressed in normal colon tissues but its expression level is decreased in colon cancer tissues collected from the same patients. Immunofluorescence microscopy shows that CHK colocalizes with Src in normal colon FHC cells. Overexpression of CHK in colon cancer cells results in inactivation of Src without phosphorylating Y530 at its C-terminus. In addition, CHK suppresses anchorage-independent cell growth and cell invasion of colon cancer cells. These results reveal a potentially important role for CHK in Src activation and tumorigenicity in colon cancer cells.

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Section: Resultsmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Decreased CHK protein levels are associated with Src activation in colon cancer cells

et al. 2007

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“…In this context, several candidates have been suggested to disrupt the SH2-pTyr529 intramolecular interaction. These include growth factor receptors, through their association with SFK-SH2 (Mao et al, 1997), and tyrosine phosphatases that dephosphorylate pTyr529 (Liang et al, 2007;Zhu et al, 2007;Zheng et al, 2008). Although probably activated in a subset of tumours, they may not account for the kinase deregulation observed in CRC.…”

Section: Introductionmentioning

confidence: 99%

Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization

et al. 2009

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The nonreceptor tyrosine kinases of the Src family (SFK) are frequently deregulated in human colorectal cancer (CRC), and they have been implicated in tumour growth and metastasis. How SFK are activated in this cancer has not been clearly established. Here, we show that the SFK-dependent invasion is induced by inactivation of the negative regulator C-terminal Src kinase, Csk. While the level of Csk was inconsistent with SFK activity in colon cancer cells, its membrane translocation, needed for efficient regulation of membrane-localized SFK activity, was impaired. Accordingly, Csk downregulation did not affect SFK oncogenic activity in these cells, whereas expression of a membrane-localized form of this kinase affected their invasive activity. Downregulation of the transmembrane and rafts-localized Csk-binding protein/ phosphoprotein associated with glycosphingolipid-enriched microdomain (PAG), was instrumental for the cytoplasmic accumulation of Csk. Re-expression of PAG in cells from late-stage CRC inhibited SFK invasive activity in a Cskdependent manner. Conversely, inactivation of its residual expression in early-stage CRC cells promoted SFK invasive activity. Finally, this mechanism was specific to CRC as Csk coupling to SFK was readily detected in breast cancer cells. Therefore, Csk mis-localization defines a novel mechanism for SFK oncogenic activation in CRC cells.

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“…PTP1B protein levels have been observed to be upregulated in various human cancers such as breast and ovarian cancers (13,14). Ablation or inhibition of PTP1B activity can abrogate the malignant properties of prostate cancer cells, whereas PTP1B overexpression promoted the growth of gastric and colon tumor cells (15)(16)(17). In our studies, we identified PTP1B as a downstream effector of the CRT pathway.…”

Section: Discussionmentioning

confidence: 55%

PTP1B Contributes to Calreticulin-Induced Metastatic Phenotypes in Esophageal Squamous Cell Carcinoma

Wang

Hao

et al. 2013

Molecular Cancer Research

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Calreticulin (CRT) is a Ca 2þ -binding chaperone protein that alters cellular Ca 2þ -homeostasis in the endoplasmic reticulum (ER). Previously it was shown that CRT was overexpressed in esophageal squamous cell carcinoma (ESCC), and elevated CRT expression promoted the migration and invasion of ESCC cells. In the present study, the mechanisms underlying the role of CRT in esophageal carcinoma progression were investigated. Critically, depletion of CRT or protein-tyrosine phosphatase 1B (PTP1B) reduced ESCC cell migration and metastasis to the lung, whereas restoration of PTP1B protein levels rescued cell migration in CRT-silenced cells. Knockdown of CRT decreased PTP1B protein expression by reducing phosphorylation at the Y694 site of STAT5A, whereas knockdown of PTP1B reduced ERK1/2 phosphorylation at T204. Immunohistochemical analysis of CRT and PTP1B expression in ESCC patient tissues was strongly correlated. Importantly, PTP1B expression was associated with poor survival in patients with CRT overexpression. Overall, these data indicate a novel signaling pathway connecting CRT, STAT5A, PTP1B, and ERK1/2 in the regulation of ESCC cell migration.Implications: These findings suggest that PTP1B is a downstream effector of CRT signaling, promotes tumor progression, and can potentially be used as a new drug target for ESCC. Mol Cancer Res; 11(9); 986-94. Ó2013 AACR. IntroductionSquamous cell carcinoma is the predominant esophageal cancer occurring in the Chinese population and is correlated with a poor prognosis and a 5-year survival rate of 15% to 25% (1). One reason for the poor prognosis is that esophageal squamous cell carcinoma (ESCC) already exhibits extensive local invasion and distant metastasis at the time of initial diagnosis (2). Therefore, having a better understanding of the molecular pathogenesis of ESCC is important for early diagnosis and effective treatment of the disease.The metastatic process consists of a number of distinct steps. Tumor invasion and migration are parts of these sequential steps. A multitude of molecular changes in tumor cells could enable these cells to acquire highly motile properties that overcome cell-cell contacts and cell-extracellular matrix barriers. In a previous study, we showed that one of such molecular alterations is the overexpression of calreticulin (CRT) in ESCCs (3).

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PTP1B Contributes to the Oncogenic Properties of Colon Cancer Cells through Src Activation

Cited by 147 publications

References 45 publications

Decreased CHK protein levels are associated with Src activation in colon cancer cells

Decreased CHK protein levels are associated with Src activation in colon cancer cells

Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization

PTP1B Contributes to Calreticulin-Induced Metastatic Phenotypes in Esophageal Squamous Cell Carcinoma

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