Ect2 links the PKCι–Par6α complex to Rac1 activation and cellular transformation

Abstract

Protein kinase Cι (PKCι) promotes non-small cell lung cancer (NSCLC) by binding to Par6α and activating a Rac1-Pak-Mek1,2-Erk1,2 signaling cascade. The mechanism by which the PKCι-Par6α complex regulates Rac1 is unknown. Here we show that Ect2, a guanine nucleotide exchange factor (GEF) for Rho family GTPases, is coordinately amplified and overexpressed with PKCι in NSCLC tumors. RNAi-mediated knock down of Ect2 inhibits Rac1 activity and blocks transformed growth, invasion and tumorigenicity of NSCLC cells. Expression of constitutively active Rac1 (RacV12) restores transformation to Ect2-deficient cells. Interestingly, the role of Ect2 in transformation is distinct from its well-established role in cytokinesis. In NSCLC cells, Ect2 is mislocalized to the cytoplasm where it binds the PKCι-Par6α complex. RNAi-mediated knock down of either PKCι or Par6α causes Ect2 to redistribute to the nucleus, indicating that the PKCι-Par6α complex regulates the cytoplasmic localization of Ect2. Our data indicate that Ect2 and PKCι are genetically and functionally linked in NSCLC, acting to coordinately drive tumor cell proliferation and invasion through formation of an oncogenic PKCι-Par6α-Ect2 complex.

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

“…ECT2, a proposed oncogene in NSCLC (7), is the other newly discovered binding partner of FXR1. ECT2 is phosphorylated by PRKCI and associated with PAR complex to drive transformed lung cancer cell growth and invasion via activation of ERK signaling cascade (14,25). Here, we provide compelling evidence for ECT2 as a novel mRNA target of FXR1 in lung cancer.…”

“…More evidence that multiple oncogenic drivers in 3q amplicon cooperate to promote tumorigenesis is indeed emerging. Justilien et al first reported a mechanism by which PRKCI forms a complex with ECT2-PAR6A to drive transformed growth through activation of a RAC1-PAK-MEK1-ERK1,2 signaling axis in NSCLC (14,25). Recently, the same group reported a functional link of PRKCI and SOX2 to activate hedgehog signaling in lung SCC (30 We also demonstrate that although genomic amplification is a key mechanism of FXR1 gene overexpression, it is the gene expression level that drives tumor progression in vitro and in vivo.…”

“…PRKCI is also one of top 20 candidate driver genes we identified using a novel integrative computational analysis (9). ECT2 and PRKCI have been reported to promote lung tumor cell growth through the extracellular signal-regulated kinases (ERK) signaling pathway by forming a complex with PARD6A (14). The overexpression and coexpression of these three genes were validated in two independent gene expression datasets that have both SCCs and matched normal samples including TCGA (Fig.…”

The metastatic cancer cell cortex: An adaptation to enhance robust cell division in novel environments?

“…In doing so, rounding makes mitosis robust to the environment. Moreover, this may explain the identification of key regulators of mitotic rounding, particularly Ect2 and the ERM family proteins, as oncogenes associated with metastasis and capable of transforming cells to grow in soft agar [28,30]. If these ideas are borne out in experiments, it will be important to reassess the roles of the many other actin cytoskeletal regulators that have been implicated in cancer progression.…”

“…Ect2 is up-regulated in a number of cancers including lung, brain, ovarian and bladder [27], and when silenced by RNAi, leads to reduced invasion, tumorigenicity and growth in soft agar in lung cancer cells [28]. Similarly, Ezrin is over-expressed in a huge range of cancer types [29] and has been shown to be essential for metastasis and anchorage independent growth in soft agar [30].…”