Mutant K-Ras Activation of the Proapoptotic MST2 Pathway Is Antagonized by Wild-Type K-Ras

Abstract

K-Ras mutations are frequent in colorectal cancer (CRC), albeit K-Ras is the only Ras isoform that can elicit apoptosis. Here, we show that mutant K-Ras directly binds to the tumor suppressor RASSF1A to activate the apoptotic MST2-LATS1 pathway. In this pathway LATS1 binds to and sequesters the ubiquitin ligase Mdm2 causing stabilization of the tumor suppressor p53 and apoptosis. However, mutant Ras also stimulates autocrine activation of the EGF receptor (EGFR) which counteracts mutant K-Ras-induced apoptosis. Interestingly, this protection requires the wild-type K-Ras allele, which inhibits the MST2 pathway in part via AKT activation. Confirming the pathophysiological relevance of the molecular findings, we find a negative correlation between K-Ras mutation and MST2 expression in human CRC patients and CRC mouse models. The small number of tumors with co-expression of mutant K-Ras and MST2 has elevated apoptosis rates. Thus, in CRC, mutant K-Ras transformation is supported by the wild-type allele.

Bcl-2 stabilization by paxillin confers 5-fluorouracil resistance in colorectal cancer

“…K-ras and BRAF mutations were linked with activation of AKT and ERK signaling pathway. [19][20][21][22][23][24] Therefore, the involvement of AKT and ERK activation in the increase of Bcl-2 expression can be expected in colorectal cancer. All cell lines used in this study harbored either K-ras mutation or BRAF mutation (Supplementary Figure 7a).…”

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

“…In contrast, the regulation of MST1/2 by RASSF1A has been studied more extensively. In human cells, RASSF1A signals through MST/LATS1 to induce apoptosis [105][106][107], and can also trigger apoptosis by MST1/NDR signalling [108]. Part of the mode of action appears to be that RASSF1A protects MST1/2 from dephosphorylation by PP2A to induce apoptosis [109].…”

“…Part of the mode of action appears to be that RASSF1A protects MST1/2 from dephosphorylation by PP2A to induce apoptosis [109]. Whatever the case, RASSF1A has been repeatedly reported as an activator of MST1/2 signalling [105][106][107][108]110]. RASSF1A can form complexes with MST1/2 and WW45 through conserved SARAH domains [71,82,83,111], which seems to play a role in Hippo dependent and independent apoptotic signalling [112].…”

“…Furthermore, the contradiction between Drosophila and human data regarding RASSF signalling should be clarified. In flies, the Tapon laboratory reported that dRASSF antagonises Hippo signalling [72], while in human cells RASSF1A activates MST/LATS/ NDR signalling [105][106][107][108]110]. Possibly these differences can be explained by considering other RASSF family members [118,119].…”

Contribution of LATS1 and LATS2 promoter methylation in OSCC development

“…Another impressive role of LATS2 in response to damage is apoptosis triggering Chi-square test *M methyl, U unmethyl through phosphorylation of ASPP1 in Lats2-ASPP1-p53 axis which shunts p53 to pro-apoptotic promoters and promotes apoptosis (Aylon et al 2010). Unlike LATS2 gene, LATS1 gene achieves mentioned activities through RASSF1A → MST2 → LATS1 pathway, which finally induces apoptosis through blocking Mdm2 and leading to p53 stabilization (Matallanas et al 2011). LATS1/2 on the hippo signaling pathway phosphorylate YAP/TAZ dimer which leads to shift the dimer from cytoplasm to nuclear.…”