HPK1, also named MAP4K1, is a mammalian Ste20-related serine/threonine kinase and has been shown to inhibit Erk and activate NF?B and JNK pathways (1). While a number of studies have identified the role of HPK1 in proliferation, differentiation and apoptosis in hematopoietic cells, the role of HPK1 in malignant transformation, proliferation, and invasion in malignancies has not been examined. Recently, we demonstrated that HPK1 protein is expressed in normal pancreatic ducts, but is lost in >95% of pancreatic ductal carcinoma (PDC) samples. The loss of HPK1 protein is strongly associated with the progression from low-grade pancreatic intraepithelial neoplasia (PanIN) to invasive PDC. More importantly, restoring wild type HPK1 protein expression in PDC cells resulted in cell cycle arrest and growth inhibition, which is due in part to up- regulation of p21 and p27 (2). Thus, our data showed, for the first time, that HPK1 may function as a novel tumor suppressor and its loss plays a critical role in the development of PDC. In addition, we have also demonstrated that loss of HPK1 in PDC is due to proteasome-mediated protein degradation, but not at the mRNA levels and that HPK1 kinase activity is required for the loss of HPK1 protein in PDC (2). Little is known about the regulation of HPK1 in vivo. Recently, we have identified Fbw8 as the E3 ligase that is responsible for proteasome-mediated degradation of HPK1 protein in PDC. In this proposal, we will examine the novel molecular mechanisms by which Fbw8 targets HPK1 protein for degradation and the oncogenic functions of Fbw8 in pancreatic cancer. Accomplishment of the proposed studies will not only reveal the novel molecular pathways of HPK1 regulation in pancreatic cancer, but also identify new targets for pancreatic cancer treatment. We have the following two Specific Aims:
Specific Aim 1 : To examine the mechanism of ubiquitin E3 ligase, Fbw8, in proteasome-mediated degradation of HPK1 protein in pancreatic cancer.
Specific Aim 2 : To examine the function of Fbw8-mediated HPK1 degradation in tumor growth and metastasis of pancreatic cancer.
Proteasome-mediated Degradation of Hematopoietic Progenitor Kinase 1 in Pancreatic Cancer We recently demonstrated that HPK1 function as a novel tumor suppressor and that proteasome-mediated degradation of HPK1 protein is strongly associated with the progression from low-grade pancreatic intraepithelial neoplasia (PanIN) to invasive pancreatic cancer. In this proposal, we will examine the detailed molecular mechanisms of proteasome-mediated degradation of HPK1 protein and to examine the possible oncogenic functions of the newly identified ubiquitin-E3 ligase, Fbw8, that is responsible for HPK1 degradation in pancreatic cancer. Accomplishment of the proposed studies will reveal novel pathways of HPK1 regulation in pancreatic cancer and identify novel targets for pancreatic cancer treatment.
|Fischer, Laurice K; Katz, Matthew H; Lee, Sun M et al. (2016) The number and ratio of positive lymph nodes affect pancreatic cancer patient survival after neoadjuvant therapy and pancreaticoduodenectomy. Histopathology 68:210-20|
|Wang, Hua; Maitra, Anirban; Wang, Huamin (2016) The emerging roles of F-box proteins in pancreatic tumorigenesis. Semin Cancer Biol 36:88-94|
|Shroff, Stuti; Rashid, Asif; Wang, Hua et al. (2014) SOX9: a useful marker for pancreatic ductal lineage of pancreatic neoplasms. Hum Pathol 45:456-63|
|Wang, Hua; Chen, Yue; Lin, Ping et al. (2014) The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8) ubiquitin ligase promotes degradation of hematopoietic progenitor kinase 1. J Biol Chem 289:4009-17|
|Zenali, Maryam; Overman, Michael J; Rashid, Asif et al. (2013) Clinicopathologic features and prognosis of duodenal adenocarcinoma and comparison with ampullary and pancreatic ductal adenocarcinoma. Hum Pathol 44:2792-8|
|Shroff, Stuti; Overman, Michael J; Rashid, Asif et al. (2013) The expression of PTEN is associated with improved prognosis in patients with ampullary adenocarcinoma after pancreaticoduodenectomy. Arch Pathol Lab Med 137:1619-26|
|Chatterjee, Deyali; Katz, Matthew H; Rashid, Asif et al. (2013) Pancreatic intraepithelial neoplasia and histological changes in non-neoplastic pancreas associated with neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma. Histopathology 63:841-51|
|Foo, Wai Chin; Rashid, Asif; Wang, Hua et al. (2013) Loss of phosphatase and tensin homolog expression is associated with recurrence and poor prognosis in patients with pancreatic ductal adenocarcinoma. Hum Pathol 44:1024-30|
|Li, Lei; Othman, Mohammad; Rashid, Asif et al. (2013) Solid pseudopapillary neoplasm of the pancreas with prominent atypical multinucleated giant tumour cells. Histopathology 62:465-71|
|Chatterjee, Deyali; Katz, Matthew H; Rashid, Asif et al. (2012) Histologic grading of the extent of residual carcinoma following neoadjuvant chemoradiation in pancreatic ductal adenocarcinoma: a predictor for patient outcome. Cancer 118:3182-90|
Showing the most recent 10 out of 15 publications