Leupaxin stimulates adhesion and migration of prostate cancer cells through modulation of the phosphorylation status of the actin-binding protein caldesmon

Abstract

The focal adhesion protein leupaxin (LPXN) is overexpressed in a subset of prostate cancers (PCa) and is involved in the progression of PCa. In the present study, we analyzed the LPXN-mediated adhesive and cytoskeletal changes during PCa progression. We identified an interaction between the actin-binding protein caldesmon (CaD) and LPXN and this interaction is increased during PCa cell migration. Furthermore, knockdown of LPXN did not affect CaD expression but reduced CaD phosphorylation. This is known to destabilize the affinity of CaD to F-actin, leading to dynamic cell structures that enable cell motility. Thus, downregulation of CaD increased migration and invasion of PCa cells. To identify the kinase responsible for the LPXN-mediated phosphorylation of CaD, we used data from an antibody array, which showed decreased expression of TGF-beta-activated kinase 1 (TAK1) after LPXN knockdown in PC-3 PCa cells. Subsequent analyses of the downstream kinases revealed the extracellular signal-regulated kinase (ERK) as an interaction partner of LPXN that facilitates CaD phosphorylation during LPXN-mediated PCa cell migration. In conclusion, we demonstrate that LPXN directly influences cytoskeletal dynamics via interaction with the actin-binding protein CaD and regulates CaD phosphorylation by recruiting ERK to highly dynamic structures within PCa cells.

Tumour-suppressor microRNAs regulate ovarian cancer cell physical properties and invasive behaviour

“…Another predicted target of miR-508-3p is leupaxin ( LPXN ) (TargetScan = 0.97, mirSVR = 0.73, miRmap = 0.62), which is a member of the paxillin family of focal adhesion proteins. Leupaxin directly affects cytoskeletal organization and dynamics through its interaction with the actin-binding protein caldesmon ( CALD1 ) [54,55]. …”

“…Leupaxin interacts with integrins and regulates the lifetime of adhesion sites [121]; since actin polymerization is required for focal adhesion formation, we speculate that reduced LPXN expression may alter actin remodelling, and thereby affect cell deformability. Leupaxin is also an interaction partner of the actin-binding protein caldesmon, and thereby directly affects cytoskeletal structure and dynamics [54,55]. However, analysis of LPXN expression using TCGA data through cBioPortal reveals upregulation in only 4% of patients [122,123] (electronic supplementary material, figure S7), and may therefore have limited clinical impact.…”

Leupaxin Promotes Bladder Cancer Proliferation, Metastasis, and Angiogenesis Through the PI3K/AKT Pathway

“…Early study showed that LPXN could form a signaling complex with protein tyrosine kinases Pyk2, c-Src, and the cytosolic protein tyrosine phosphatase-proline-, glutamate-, serine-, and threonine-rich sequence to modulate prostate cancer cell migration [17]. In another study, Dierks et al demonstrated that LPXN stimulated prostate cancer cell adhesion and migration through regulation of the phosphorylation of the actin-binding protein caldesmon [18]. In hepatocellular carcinoma (HCC), LPXN contributes to HCC cell proliferation and cell-cycle progression via interacting with β-catenin and enhance its transcriptional activity [19].…”

Leupaxin Expression Is Dispensable for B Cell Immune Responses

“…Moreover, in A20 and cos1 cell lines and splenocytes, Lpxn inhibits the Ras pathway that is crucial during B cell activation (22,23). Lpxn dysregulation was also shown to participate to tissue invasion by promoting cancerous cell adhesion and migration (19,24). In addition, an integrin-independent role for Lpxn in BCR signaling was previously reported (25).…”