FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2-dependent apoptosis

Abstract

Cancer cells balance with the equilibrium of cell death and growth to expand and metastasize. The activity of mammalian sterile20-like kinases (MST1/2) has been linked to apoptosis and tumor suppression via YAP/Hippo pathway-independent and -dependent mechanisms. Using a kinase substrate screen, we identified here MST1 and MST2 among the top substrates for fibroblast growth factor receptor 4 (FGFR4). In COS-1 cells, MST1 was phosphorylated at Y433 residue in an FGFR4 kinase activity-dependent manner, as assessed by mass spectrometry. Blockade of this phosphorylation by Y433F mutation induced MST1 activation, as indicated by increased threonine phosphorylation of MST1/2, and the downstream substrate MOB1, in FGFR4-overexpressing T47D and MDA-MB-231 breast cancer cells. Importantly, the specific knockdown or short-term inhibition of FGFR4 in endogenous models of human HER2 + breast cancer cells likewise led to increased MST1/ 2 activation, in conjunction with enhanced MST1 nuclear localization and generation of N-terminal cleaved and autophosphorylated MST1. Unexpectedly, MST2 was also essential for this MST1/N activation and coincident apoptosis induction, although these two kinases, as well as YAP, were differentially regulated in the breast cancer models analyzed. Moreover, pharmacological FGFR4 inhibition specifically sensitized the HER2 + MDA-MB-453 breast cancer cells, not only to HER2/EGFR and AKT/mTOR inhibitors, but also to clinically relevant apoptosis modulators. In TCGA cohort, FGFR4 overexpression correlated with abysmal HER2 + breast carcinoma patient outcome. Therefore, our results uncover a clinically relevant, targetable mechanism of FGFR4 oncogenic activity via suppression of the stress-associated MST1/2induced apoptosis machinery in tumor cells with prominent HER/ERBB and FGFR4 signaling-driven proliferation.

Enhanced autocrine FGF19/FGFR4 signaling drives the progression of lung squamous cell carcinoma, which responds to mTOR inhibitor AZD2104

“…Mutated FGFR4 was found to induce local growth and enhance metastasis in these cancers [23]. In breast cancer, FGFR4 resist cancer cell apoptosis by phosphorylating MST1 [24]. Hence, FGFR4, owing to the oncogenic activity, may serve as a potential predictive biomarker for anti-FGFR4 targeted therapy [25].…”

<p>MOB1 Inhibits Malignant Progression of Colorectal Cancer by Targeting PAK2</p>

“…9,10 Previous studies have reported that MOB1 expression might have great influence on the progression of some malignant tumors such as pancreatic cancer and breast cancer; however, whether it could affect the development of CRC still has not been studied. 16,17 In this study, MOB1 expression was found remarkably upregulated in CRC tissues and cell lines. In addition, we found that patients with low MOB1 expression had higher metastasis incidence and pathological stage and lower progression-free survival rate, suggesting a worse prognosis.…”

“…15 Recent studies have suggested that MOB1 may be engaged in the regulation of proliferation, apoptosis, migration and invasion of pancreatic cancer, breast cancer and other malignant tumor cells. 16,17 Therefore, the study of MOB1 in CRC not only helps to clarify the pathogenesis of this tumor but also provides valuable targets for its diagnosis and treatment.…”

Hippo Signaling Pathway as a Central Mediator of Receptors Tyrosine Kinases (RTKs) in Tumorigenesis

“…However, higher doses greatly increase Hippo expression and cause YAP phosphorylation, triggering lens fiber differentiation [128]. Another study investigating the mechanism underlying breast cancer cell resistance to MST1/2-dependent apoptosis showed that FGFR4 phosphorylates MST1/2 and inhibits its activation [129].…”

“…Reduced MST1/2 phosphorylation by VEGFR and YAP/TAZ effect on VEGFR-induced angiogenesis [118] Effect of actin cytoskeleton dynamics on YAP/TAZ through VEGFR2-SFKs-Rho GTPase [119] Tie (Altiratinib) YAP1/STAT3 complex regulate ANG2 expression promoting angiogenesis [121] YAP-dependent expression of ANG2 is regulated by cellular confluency [122] YAP/TAZ knockdown decreases Tie2 expression and blocks vascular formation [123] FGFR (erdafitinib, Infigratinib) FGF2-SAPK/JNK MAP kinase signaling downregulates TAZ [124] YAP/TBX5 complex controls FGFR1, -2, and -4 expression and FGF5 reduces LATS cellular levels [126] FGF1/FGFR3, MAPK/ERK mediated, increase of ETV5 elevates TAZ activity [127] Different doses of FGF have different effects on hippo and cause distinct outcomes in lens cells [128] FGFR4 mediated breast cancer cell MST1/2 resistance [129] Direct phosphorylation of YAP by FGFR, RET, and MERTK receptors [130] ALK (crizotinib, brigatinib) ALK inhibits LATS and activates YAP to drive tumorigenesis phenotype [132]…”