PYK2 Is Involved in Premalignant Acinar Cell Reprogramming and Pancreatic Ductal Adenocarcinoma Maintenance by Phosphorylating β-CateninY654

Abstract

Background & AimsIdentification and validation of new functionally relevant and pharmacologically actionable targets for pancreatic ductal adenocarcinoma (PDAC) remains a great challenge. Premalignant acinar cell reprogramming (acinar-to-ductal metaplasia [ADM]) is a precursor of pancreatic intraepithelial neoplasia (PanIN) lesions that can progress to PDAC. This study investigated the role of proline-rich tyrosine kinase 2 (PYK2) in mutant Kras-induced and pancreatitis-associated ADM and PanIN formation, as well as in PDAC maintenance.MethodsGenetically engineered mouse models of mutant Kras (glycine 12 to aspartic acid) and Pyk2 deletion were used for investigating the role of PYK2 in PDAC genesis in mice. In vitro ADM assays were conducted using primary pancreatic acinar cells isolated from mice. Immunohistochemistry, immunofluorescence, and a series of biochemical experiments were used to investigate upstream regulators/downstream targets of PYK2 in pancreatic carcinogenesis. PDAC cell line xenograft experiments were performed to study the role of PYK2 and its downstream target in PDAC maintenance.ResultsPYK2 was increased substantially in ADM lesions induced by mutant Kras or inflammatory injury. Pyk2 deletion remarkably suppressed ADM and PanIN formation in a mutant Kras-driven and pancreatitis-associated PDAC model, whereas PYK2 knockdown substantially inhibited PDAC cell growth in vitro and in nude mice. This study uncovered a novel yes-associated protein 1/transcriptional co-activator with PDZ binding motif/signal transducer and activator of transcription 3/PYK2/β-catenin regulation axis in PDAC. Our results suggest that PYK2 contributes to PDAC genesis and maintenance by activating the Wnt/β-catenin pathway through directly phosphorylating β-cateninY654.ConclusionsThe current study uncovers PYK2 as a novel downstream effector of mutant KRAS signaling, a previously unrecognized mediator of pancreatitis-induced ADM and a novel intervention target for PDAC.

Protocadherins at the Crossroad of Signaling Pathways

“…Pcdhs could also modulate the activity of kinases and phosphatases that play a role in Wnt signaling. For instance, signaling downstream of Fak and Pyk2 has been linked to several Wnt pathway modules ( Chen et al, 2002 ; Gao et al, 2015 , 2019 ; Sun et al, 2016 ; Zheng et al, 2019 ).…”

“…Moreover, active Pyk2 and FAK can phosphorylate GSK3β, ultimately resulting in the degradation of GSK3β and the accumulation of β-catenin, leading to increased Wnt signaling. In addition, active Pyk2 can also phosphorylate β-catenin ( Gao et al, 2015 , 2019 ). CPcdhs regulate WRC activity by binding to Pyk2 and FAK, hence preventing their autophosphorylation and subsequent activation.…”

PYK2 at the Intersection of Signaling Pathways in Pancreatic Cancer

“…Answering that question is crucial to understand tumor biology and, more importantly, to identify the most likely targets for therapeutic interventions. In the current article by Gao et al, 1 multiple seemingly disparate signaling molecules, both previously published and novel, are shown to lie within a direct pathway that regulates PDAC development and tumor growth.…”

“…Gao et al 1 investigated the role of PYK2 in PDAC development and maintenance. PYK2 is closely related to the non-receptor tyrosine kinase FAK and was overexpressed in more than half of PDAC tissues examined.…”

“…Similarly, inflammation is critical for initiation of PDAC but continues to play roles in tumor development, maintenance, and spread. Gao et al 1 found that PYK2 responds to inflammation as well as KRAS activation and has a continuing role in tumorigenesis from initiation to tumor maintenance. Although mutant KRAS appears to be resistant to therapeutic intervention and inflammation in the pancreas is perhaps too complex for effective targeting at present, it may be possible to target pathways downstream of KRAS and inflammation.…”