Tyrosine-protein phosphatase non-receptor type 12 expression is a good prognostic factor in resectable non-small cell lung cancer

Cao, Xun; Chen, Yanzhen; Luo, Ruo‑Zhen; Zhang, Lin; Zhang, Songliang; Zeng, Jun; Jiang, Yuchuan; Yang, Han; Wen, Zhesheng

doi:10.18632/oncotarget.3588

Cited by 20 publications

(16 citation statements)

References 34 publications

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“…This alteration was more common in TNBC. Likewise, decreased expression of PTPN12 was reported in other human malignancies, including non-small-cell lung carcinoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma, and hepatocellular carcinoma (18)(19)(20)(21). In all cases, loss of PTPN12 correlated with aggressiveness and poor prognosis.…”

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confidence: 63%

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Loss of PTPN12 Stimulates Progression of ErbB2-Dependent Breast Cancer by Enhancing Cell Survival, Migration, and Epithelial-to-Mesenchymal Transition

Davidson

Souza

et al. 2015

Molecular and Cellular Biology

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e PTPN12 is a cytoplasmic protein tyrosine phosphatase (PTP) reported to be a tumor suppressor in breast cancer, through its capacity to dephosphorylate oncogenic receptor protein tyrosine kinases (PTKs), such as ErbB2. However, the precise molecular and cellular impact of PTPN12 deficiency in breast cancer progression remains to be fully clarified. Here, we addressed this issue by examining the effect of PTPN12 deficiency on breast cancer progression in vivo, in a mouse model of ErbB2-dependent breast cancer using a conditional PTPN12-deficient mouse. Our studies showed that lack of PTPN12 in breast epithelial cells accelerated breast cancer development and lung metastases in vivo. PTPN12-deficient breast cancer cells displayed enhanced tyrosine phosphorylation of the adaptor Cas, the adaptor paxillin, and the kinase Pyk2. They exhibited no detectable increase in ErbB2 tyrosine phosphorylation. PTPN12-deficient cells were more resistant to anoikis and had augmented migratory and invasive properties. Enhanced migration was corrected by inhibiting Pyk2. PTPN12-deficient breast cancer cells also acquired partial features of epithelial-to-mesenchymal transition (EMT), a feature of more aggressive forms of breast cancer. Hence, loss of PTPN12 promoted tumor progression in a mouse model of breast cancer, supporting the notion that PTPN12 is a tumor suppressor in human breast cancer. This function was related to the ability of PTPN12 to suppress cell survival, migration, invasiveness, and EMT and to inhibit tyrosine phosphorylation of Cas, Pyk2, and paxillin. These findings enhance our understanding of the role and mechanism of action of PTPN12 in the control of breast cancer progression. P rotein tyrosine phosphatases (PTPs) play a key role in normal cellular processes, such as proliferation, migration, adhesion, differentiation, and immune cell activation (1-3). Depending on the phosphatase and the cell type, they also have the ability either to suppress or to promote malignant transformation (3). PTPN12, also referred to as PTP-PEST (PTP-proline, glutamic acid, serine, and threonine rich), is a cytoplasmic PTP expressed in a wide spectrum of cell types (4). Studies of PTPN12-deficient mice showed that PTPN12 is a critical positive regulator of migration and adhesion in embryonic fibroblasts, endothelial cells, T cells, macrophages, and dendritic cells (5-11). This function relates to the capacity of PTPN12 to dephosphorylate cytoskeletonassociated substrates such as protein tyrosine kinases (PTKs) Pyk2 and FAK or the adaptors Cas, paxillin, and PSTPIP-1. These substrates are components of the cellular machinery controlling migration and adhesion. PTPN12 can also regulate other substrates, including receptor PTKs, such as ErbB2 and the adaptor . Proteomic data suggested that the ability of PTPN12 to regulate Shc might be critical for conversion of Shc-dependent proliferative signals into migratory signals (15). Several PTPN12 substrates, and in particular, Cas, paxillin, and Shc, also directly associate with PTPN12....

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confidence: 63%

“…This could also be the case for other types of human cancer in which loss of PTPN12 is more often seen in aggressive subtypes. These include lung cancer, nasopharyngeal cancer, esophageal cancer, and hepatocellular carcinoma (14,18,20,21).…”

Section: Discussionmentioning

confidence: 99%

Loss of PTPN12 Stimulates Progression of ErbB2-Dependent Breast Cancer by Enhancing Cell Survival, Migration, and Epithelial-to-Mesenchymal Transition

Davidson

Souza

et al. 2015

Molecular and Cellular Biology

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“…PTPN12, a recently characterized tumor suppressor, has been demonstrated as a pivotal regulator of EGFR/HER2 signaling and is required for embryonic development (Cao et al, 2012(Cao et al, , 2015Zheng et al, 2013;Sun et al, 2011;Souza et al, 2012;Luo et al, 2014;Albeck and Brugge, 2011). PTPN12 knockout mice are embryonic lethal.…”

Section: Introductionmentioning

confidence: 99%

Crystal Structure and Substrate Specificity of PTPN12

Yang

Liu

et al. 2016

Cell Reports

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PTPN12 is an important tumor suppressor that plays critical roles in various physiological processes. However, the molecular basis underlying the substrate specificity of PTPN12 remains uncertain. Here, enzymological and crystallographic studies have enabled us to identify two distinct structural features that are crucial determinants of PTPN12 substrate specificity: the pY+1 site binding pocket and specific basic charged residues along its surface loops. Key structurally plastic regions and specific residues in PTPN12 enabled recognition of different HER2 phosphorylation sites and regulated specific PTPN12 functions. In addition, the structure of PTPN12 revealed a CDK2 phosphorylation site in a specific PTPN12 loop. Taken together, our results not only provide the working mechanisms of PTPN12 for desphosphorylation of its substrates but will also help in designing specific inhibitors of PTPN12.

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“…It was known that PTPN12 is a multifunctional protein involved in many physiologic processes, such as cytoskeleton remodeling (33), tumor suppression (3), T cell-dependent immune responses (34), embryonic development (25), and bone resorption (24). In particular, PTPN12 is regarded as a very important newly identified tumor suppressor whose expression is down regulated in breast (3), lung (35), and colorectal cancers and in many others (36). In addition to the PTPN12 protein level change, it was unclear what other regulatory mechanisms occur in cancer.…”

Section: Discussionmentioning

confidence: 99%

Switching of the substrate specificity of protein tyrosine phosphatase N12 by cyclin‐dependent kinase 2 phosphorylation orchestrating 2 oncogenic pathways

Ning

et al. 2017

FASEB j.

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The protein tyrosine phosphatase nonreceptor type 12 (PTPN12) is a multifunctional protein and has elicited much research attention because its decreased protein level has been associated with poor prognosis of several types of cancers. Recently, we have solved the crystal structure of the phosphatase domain of PTPN12, which disclosed a specific PTPN12-insert-loop harboring a cyclin-dependent kinase 2 (CDK2) phosphorylation site. However, the functional significance of this phosphorylation is undefined. In the present study, we found that S19 site phosphorylation of PTPN12 by CDK2 discharged its antitumor activity by down-regulation of its inhibitory role in cell migration, but not affecting its other regulatory functions. Phosphorylation of PTPN12 at the S19 site changed its substrate interface, and by doing so, selectively decreased its activity toward the human epidermal growth factor receptor 2 (HER2)- pY site, but not other HER2 phosphorylation sites or other known PTPN12 substrates. A further in-depth mechanism study revealed that the phosphorylation of PTPN12 by CDK2 impaired recruitment of the serine/threonine-protein kinase 1 (PAK1) to HER2, resulted in the blockade of the HER2-pY-PAK1-T signaling pathway, thus increased tumor cell motility. Taken together, our results identified a new phosphorylation-based substrate recognition mechanism of PTPN12 by CDK2, which orchestrated signaling crosstalk between the oncogenic CDK2 and HER2 pathways. The newly identified governing mechanism of the substrate selectivity of a particular phosphatase was previously unappreciated and exemplifies how a phospho-network is precisely controlled in different cellular contexts.-Li, H., Yang, D., Ning, S., Xu, Y., Yang, F., Yin, R., Feng, T., Han, S., Guo, L., Zhang, P., Qu, W., Guo, R., Song, C., Xiao, P., Zhou, C., Xu, Z., Sun, J.-P., Yu, X. Switching of the substrate specificity of protein tyrosine phosphatase N12 by cyclin-dependent kinase 2 phosphorylation orchestrating 2 oncogenic pathways.

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Tyrosine-protein phosphatase non-receptor type 12 expression is a good prognostic factor in resectable non-small cell lung cancer

Cited by 20 publications

References 34 publications

Loss of PTPN12 Stimulates Progression of ErbB2-Dependent Breast Cancer by Enhancing Cell Survival, Migration, and Epithelial-to-Mesenchymal Transition

Loss of PTPN12 Stimulates Progression of ErbB2-Dependent Breast Cancer by Enhancing Cell Survival, Migration, and Epithelial-to-Mesenchymal Transition

Crystal Structure and Substrate Specificity of PTPN12

Switching of the substrate specificity of protein tyrosine phosphatase N12 by cyclin‐dependent kinase 2 phosphorylation orchestrating 2 oncogenic pathways

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