Hematopoietic progenitor kinase 1 down-regulates the oncogenic receptor tyrosine kinase AXL in pancreatic cancer.
Xianzhou Song, Hironari Akasaka, Hua Wang, Reza Abbasgholizadeh, Ji-Hyun Shin, Fenglin Zang, Jiayi Chen, Craig D Logsdon, Anirban Maitra, Andrew J Bean, Huamin Wang
Author Information
Xianzhou Song: Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
Hironari Akasaka: Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
Hua Wang: Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
Reza Abbasgholizadeh: Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
Ji-Hyun Shin: Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
Fenglin Zang: Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
Jiayi Chen: Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
Craig D Logsdon: Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
Anirban Maitra: Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030; Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
Andrew J Bean: Department of Neurobiology and Anatomy, University of Texas McGovern Medical School, Houston, Texas 77030.
Huamin Wang: Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030; Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030. Electronic address: hmwang@mdanderson.org.
The oncogenic receptor tyrosine kinase AXL is overexpressed in cancer and plays an important role in carcinomas of multiple organs. However, the mechanisms of AXL overexpression in cancer remain unclear. In this study, using HEK293T, Panc-1, and Panc-28 cells and samples of human pancreatic intraepithelial neoplasia (PanIN), along with several biochemical approaches and immunofluorescence microscopy analyses, we sought to investigate the mechanisms that regulate AXL over-expression in pancreatic ductal adenocarcinoma (PDAC). We found that AXL interacts with hematopoietic progenitor kinase 1 (HPK1) and demonstrate that HPK1 down-regulates AXL and decreases its half-life. The HPK1-mediated AXL degradation was inhibited by the endocytic pathway inhibitors leupeptin, bafilomycin A1, and monensin. HPK1 accelerated the movement of AXL from the plasma membrane to endosomes in pancreatic cancer cells treated with the AXL ligand growth arrest-specific 6 (GAS6). Moreover, HPK1 increased the binding of AXL to the Cbl proto-oncogene (c-Cbl); promoted AXL ubiquitination; decreased AXL-mediated signaling, including phospho-AKT and phospho-ERK signaling; and decreased the invasion capability of PDAC cells. Importantly, we show that AXL expression inversely correlates with HPK1 expression in human PanINs and that patients whose tumors have low HPK1 and high AXL expression levels have shorter survival than those with low AXL or high HPK1 expression ( < 0.001). Our results suggest that HPK1 is a tumor suppressor that targets AXL for degradation via the endocytic pathway. HPK1 loss of function may contribute to AXL overexpression and thereby enhance AXL-dependent downstream signaling and tumor invasion in PDAC.
