The Regulatory Role of KIBRA and PTPN14 in Hippo Signaling and Beyond

Wilson, Kayla E.; Yang, Nuo; Mussell, Ashley L.; Zhang, Jianmin

doi:10.3390/genes7060023

Cited by 29 publications

(32 citation statements)

References 61 publications

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“…Hence, the reduced expression of Hippo core kinases in the +DDR/+COL1 HT1080 tumours may underlie the ability of these tumours to display accelerated growth. Consistent with the tumour suppressive role of the Hippo pathway, we found that KIBRA, an upstream regulator of the Hippo pathway, and also considered a tumour suppressor [150][151][152][153] , was significantly downregulated in +DDR2/+COL1 but not in +DDR1b/+COL1 tumours. This suggests that KIBRA may be a major target of DDR2 signalling in response to collagen in vivo.…”

Section: Discussionsupporting

confidence: 81%

Discoidin Domain Receptors, DDR1b and DDR2, Promote Tumour Growth within Collagen but DDR1b Suppresses Experimental Lung Metastasis in HT1080 Xenografts

Wasinski

Sohail

Bonfil

et al. 2020

Sci Rep

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the Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen. Using an inducible expression system in human HT1080 fibrosarcoma cells, we investigated the role of DDR1b and DDR2 on primary tumour growth and experimental lung metastases. Neither DDR1b nor DDR2 expression altered tumour growth at the primary site. However, implantation of DDR1b-or DDR2-expressing HT1080 cells with collagen I significantly accelerated tumour growth rate, an effect that could not be observed with collagen I in the absence of DDR induction. Interestingly, DDR1b, but not DDR2, completely hindered the ability of HT1080 cells to form lung colonies after intravenous inoculation, suggesting a differential role for DDR1b in primary tumour growth and lung colonization. Analyses of tumour extracts revealed specific alterations in Hippo pathway core components, as a function of DDR and collagen expression, that were associated with stimulation of tumour growth by DDRs and collagen I. Collectively, these findings identified divergent effects of DDRs on primary tumour growth and experimental lung metastasis in the HT1080 xenograft model and highlight the critical role of fibrillar collagen and DDRs in supporting the growth of tumours thriving within a collagen-rich stroma. The DDRs constitute a unique subfamily of receptor tyrosine kinases (RTKs) that signal in response to collagens, and therefore they represent the only RTKs that are directly activated upon contact of cells with their collagenous matrix 1-6. The DDR subfamily comprises two kinases: DDR1 and DDR2 1,2,7. The DDR1 subfamily includes six isoforms generated by alternative splicing, while there is only one form of DDR2. Among the DDR1 isoforms, DDR1a, DDR1b, and DDR1c are full length, highly homologous receptors, with the only structural difference being the presence of 37 additional residues, including two additional tyrosine residues, within the intracellular region of DDR1b and DDR1c, suggesting that these species may activate different downstream signalling pathways 1. DDR1d and DDR1e are truncated, kinase-deficient receptors of unknown function 8. DDR1f contains a full kinase domain but lacks most of the extracellular domains 9. Structurally, the DDRs are type I transmembrane

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Section: Discussionsupporting

confidence: 81%

Discoidin Domain Receptors, DDR1b and DDR2, Promote Tumour Growth within Collagen but DDR1b Suppresses Experimental Lung Metastasis in HT1080 Xenografts

Wasinski

Sohail

Bonfil

et al. 2020

Sci Rep

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“…Among this small group of transcripts were several whose encoded proteins might participate in the accelerated growth of recurrent tumors (Supplemental Figure S1A). These included Gdf3, a member of the TGF-β family of growth factors, which was up-regulated (58); Ildr2, Pcx and Dhtkd1, which regulate lipid and carbohydrate metabolism and which were all down-regulated (59-61); and three putative tumor suppressors, PLK2, PTPN14, and TSHZ2, which were also down-regulated (62)(63)(64).…”

Section: Resultsmentioning

confidence: 99%

Sequential adaptive changes in a c-Myc-driven model of hepatocellular carcinoma

Dolezal¹,

Wang²,

Kulkarni³

et al. 2017

Journal of Biological Chemistry

168

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Hepatocellular carcinoma (HCC) is a common cancer that frequently overexpresses the c-Myc (Myc) oncoprotein. Using a mouse model of Myc-induced HCC, we studied the metabolic, biochemical, and molecular changes accompanying HCC progression, regression, and recurrence. These involved altered rates of pyruvate and fatty acid β-oxidation and the likely re-directing of glutamine into biosynthetic rather than energy-generating pathways. Initial tumors also showed reduced mitochondrial mass and differential contributions of electron transport chain complexes I and II to respiration. The uncoupling of complex II's electron transport function from its succinate dehydrogenase activity also suggested a mechanism by which Myc generates reactive oxygen species. RNA sequence studies revealed an orderly progression of transcriptional changes involving pathways pertinent to DNA damage repair, cell cycle progression, insulin-like growth factor signaling, innate immunity, and further metabolic re-programming. Only a subset of functions deregulated in initial tumors was similarly deregulated in recurrent tumors thereby indicating that the latter can "normalize" some behaviors to suit their needs. An interactive and freely available software tool was developed to allow continued analyses of these and other transcriptional profiles. Collectively, these studies define the metabolic, biochemical, and molecular events accompanyingHCCevolution, regression, and recurrence in the absence of any potentially confounding therapies.

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“…There are now many reports of mutation of PTPN14 in several different human tumors (42)(43)(44)(45) and clear evidence for a role for PTPN14 in the control of diverse signaling pathways. This includes regulation of the Hippo pathway, ␤-catenin signaling, and transforming growth factor ␤ (TGF-␤) and receptor trafficking (30,31,38,46). Currently, we have no information on which of these pathways are likely to be affected as a result of E7-induced degradation of PTPN14, although our preliminary unpublished results would appear to indicate that the Hippo pathway is not directly affected by E7.…”

Section: Discussionmentioning

confidence: 99%

The PTPN14 Tumor Suppressor Is a Degradation Target of Human Papillomavirus E7

Szalmás

Tomaić

Basukala

et al. 2017

J Virol

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Activation of signaling pathways ensuring cell growth is essential for the proliferative competence of human papillomavirus (HPV)-infected cells. Tyrosine kinases and phosphatases are key regulators of cellular growth control pathways. A recently identified potential cellular target of HPV E7 is the cytoplasmic protein tyrosine phosphatase PTPN14, which is a potential tumor suppressor and is linked to the control of the Hippo and Wnt/beta-catenin signaling pathways. In this study, we show that the E7 proteins of both high-risk and low-risk mucosal HPV types can interact with PTPN14. This interaction is independent of retinoblastoma protein (pRb) and involves residues in the carboxy-terminal region of E7. We also show that high-risk E7 induces proteasome-mediated degradation of PTPN14 in cells derived from cervical tumors. This degradation appears to be independent of cullin-1 or cullin-2 but most likely involves the UBR4/p600 ubiquitin ligase. The degree to which E7 downregulates PTPN14 would suggest that this interaction is important for the viral life cycle and potentially also for the development of malignancy. In support of this we find that overexpression of PTPN14 decreases the ability of HPV-16 E7 to cooperate with activated EJ-ras in primary cell transformation assays. This study links HPV E7 to the deregulation of protein tyrosine phosphatase signaling pathways. PTPN14 is classified as a potential tumor suppressor protein, and here we show that it is very susceptible to HPV E7-induced proteasome-mediated degradation. Intriguingly, this appears to use a mechanism that is different from that employed by E7 to target pRb. Therefore, this study has important implications for our understanding of the molecular basis for E7 function and also sheds important light on the potential role of PTPN14 as a tumor suppressor.

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The Regulatory Role of KIBRA and PTPN14 in Hippo Signaling and Beyond

Cited by 29 publications

References 61 publications

Discoidin Domain Receptors, DDR1b and DDR2, Promote Tumour Growth within Collagen but DDR1b Suppresses Experimental Lung Metastasis in HT1080 Xenografts

Discoidin Domain Receptors, DDR1b and DDR2, Promote Tumour Growth within Collagen but DDR1b Suppresses Experimental Lung Metastasis in HT1080 Xenografts

Sequential adaptive changes in a c-Myc-driven model of hepatocellular carcinoma

The PTPN14 Tumor Suppressor Is a Degradation Target of Human Papillomavirus E7

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