Transgelin-2 is a novel target of KRAS-ERK signaling involved in the development of pancreatic cancer

Abstract

BackgroundThe KRAS mutation is the driving force of pancreatic ductal adenocarcinoma (PDAC). Downstream effectors of KRAS signal pathways are crucial to the development of PDAC. The purpose of this study was to investigate the relationship between KRAS mutation and transgelin-2. Transgelin-2 is highly expressed in PDAC tissues compared with adjacent normal tissues. The underlying mechanism for upregulating transgelin-2 is largely unknown.MethodsExpression of transgelin-2 was analyzed by microarray data and qRT-PCR. The effect of KRAS signaling on transgelin-2 expression was examined in PDAC cells in the presence or absence of the ERK inhibitor. The interaction of transgelin-2 with ERK was confirmed by immunoprecipitation. ERK-mediated Phosphorylation of transglein-2 was detected by in vivo and in vitro kinase assays. The gain-of-function and loss-of-function approaches were used to examine the role of phosphorylation of transgelin-2 on cell proliferation. Phosphorylation of transgelin-2 was detected by immunohistochemistry in PDAC tissues.ResultsHere we found transgelin-2 expression was induced by KRAS mutation. In the case of KRAS mutation, ERK2 interacted with 29–31 amino acids of transgelin-2 and subsequently phosphorylated the S145 residue of transgelin-2. S145 phosphorylation of transgelin-2 played important roles in cell proliferation and tumorigenesis of PDAC. In addition, S145 phosphorylation of transgelin-2 was associated with a poor prognosis in patients with PDAC.ConclusionsThis study indicated that KRAS-ERK-mediated transeglin-2 phosphorylation played an important role in the development of PDAC. Inhibition of transgelin-2 phosphorylation may be a potential therapeutic strategy for targeting PDAC with KRAS mutation.

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

“…Notably, a recent report regarding extracellular signal-regulated kinases (ERK) in KRAS -mutated PDAC, based on cell lines, pancreatic cancer organoids, and xenograft mouse-models, showed that ERK inhibition in cancer-associated stromal cells can suppress cancer-stromal interactions and PDAC metastatic potential [ 24 ]. Along these lines, Sun and colleagues, reported that inhibition of the phosphorylation of transgelin-2, a novel target of KRAS-ERK signaling, may be a potential therapeutic strategy for targeting PDAC with KRAS mutation, using PDAC cell lines, immunohistochemistry on PDAC tissues, and xenograft-mouse models [ 25 ]. Although promising, such findings are exploratory and still without a direct clinical translation.…”

Transgelin-2: Biochemical and Clinical Implications in Cancer and Asthma

“…Transgelin-2 expression is regulated at the transcriptional level by three major signaling pathways, including NF-κB, transforming growth factor β (TGFβ), and extracellular signal-regulated kinase (KRAS-ERK) pathways [10,30,31].…”

“…The third pathway modulating transgelin-2 expression is the epidermal growth factor receptor (EGFR) and KRAS-ERK signaling pathway [31]. The most relevant results of these studies are directly related to high transgelin-2 expression in pancreatic ductal adenocarcinoma (PDAC), representing the fourth leading cause of cancer-related death in the United States [35,36].…”

“…The most relevant results of these studies are directly related to high transgelin-2 expression in pancreatic ductal adenocarcinoma (PDAC), representing the fourth leading cause of cancer-related death in the United States [35,36]. The most common KRAS mutation, KRAS-G12D, is a typical hallmark in more than 90% of PDACs and induces both tumor cell proliferation and transgelin-2 expression via ERK2 [31]. These results are clinically relevant because the direct inhibition of KRAS is clinically challenging and KRAS targeted therapy has not been successful [31].…”

Actin and Actin-Associated Proteins in Extracellular Vesicles Shed by Osteoclasts

“…Transgelin-2 is a microfilament-binding protein that protects microfilaments from cofilin-mediated depolymerization, and it is a tumor-suppressor [84][85][86][87][88]. This small protein is abundant in EVs, and in principle could be involved in stabilizing a significant amount of the actin as microfilaments.…”