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Ras transformation uncouples the kinesin-coordinated cellular nutrient response.

ABSTRACT: The kinesin family members (KIFs) KIF2A and KIF2C depolymerize microtubules, unlike the majority of other kinesins, which transport cargo along microtubules. KIF2A regulates the localization of lysosomes in the cytoplasm, which assists in activation of the mechanistic target of rapamycin complex 1 (mTORC1) on the lysosomal surface. We find that the closely related kinesin KIF2C also influences lysosomal organization in immortalized human bronchial epithelial cells (HBECs). Expression of KIF2C and, to a lesser extent, KIF2A in untransformed and mutant K-Ras-transformed cells is regulated by ERK1/2. Prolonged inhibition of ERK1/2 activation with PD0325901 mimics nutrient deprivation by disrupting lysosome organization and decreasing mTORC1 activity in HBEC, suggesting a long-term mechanism for optimization of mTORC1 activity by ERK1/2. We tested the hypothesis that up-regulation of KIF2C and KIF2A by ERK1/2 caused aberrant lysosomal positioning and mTORC1 activity in a mutant K-Ras-dependent cancer and cancer model. In Ras-transformed cells, however, mTORC1 activity and lysosome organization appear independent of ERK1/2 and these kinesins although ERK1/2 activity and the kinesins are required for Ras-dependent proliferation and migration. We conclude that mutant K-Ras repurposes these signaling and regulatory proteins to support the transformed phenotype.

SUBMITTER: Zaganjor E

PROVIDER: S-EPMC4115560 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Ras transformation uncouples the kinesin-coordinated cellular nutrient response.

Zaganjor Elma E Weil Lauren M LM Gonzales Joshua X JX Minna John D JD Cobb Melanie H MH

Proceedings of the National Academy of Sciences of the United States of America 20140707 29

The kinesin family members (KIFs) KIF2A and KIF2C depolymerize microtubules, unlike the majority of other kinesins, which transport cargo along microtubules. KIF2A regulates the localization of lysosomes in the cytoplasm, which assists in activation of the mechanistic target of rapamycin complex 1 (mTORC1) on the lysosomal surface. We find that the closely related kinesin KIF2C also influences lysosomal organization in immortalized human bronchial epithelial cells (HBECs). Expression of KIF2C an ...[more]

PMID: 25002494

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Project description:IntroductionTyrosine phosphorylated signal transducer and activator of transcription 3 (pStat3) is present in numerous cancers and is required for mediating tumorigenesis. Autocrine and paracrine interleukin (IL)-6 signaling is the principal mechanism by which Stat3 is persistently phosphorylated in epithelial tumors including breast, lung, colon and gastric cancer. The Ras oncogene mediates cellular transformation without evidence of pStat3 in cultured cells. Recently, however non-tyrosine phosphorylated Stat3 was shown to have a transcriptional activating function, a role in mitochondrial function and to mediate cell migration.. Here we examined the role of Stat3 in Ras mediated transformation.MethodsHa-rasV12 transformed mammary epithelial cells (MCF10A) cells were transduced with a Stat3shRNA, IL-6shRNA and/or treated with inhibitors of Janus kinases (JAKs) to examine the role of the IL-6 signaling pathway in Ras mediated invasion and tumorigenesis.ResultsCellular migration, invasion, anchorage independent growth and tumorigenesis were largely abrogated in the Stat3-reduced cells compared to control cells. Analysis of MCF10A-Ras tumors revealed high levels of pStat3 and interleukin-6. Tumors derived from transgenic MMTV-K-Ras mice were also found to express pStat3 and IL-6. MCF10A-Ras cells, when grown in a three-dimensional Matrigel culture system revealed the appearance of the junctional protein E-Cadherin as a consequence of reducing Stat3 levels or inhibiting Stat3 activity. Decreasing IL-6 levels in the MCF10A-Ras cells abrogated tumorigenesis and reduced cell migration. By isolating Ras-expressing primary tumors and serially passaging these cells in two-dimensional culture led to a decrease in IL-6 and pStat3 levels with the reappearance of E-Cadherin.ConclusionsThe cellular and environmental context can lead to differential IL-6/pStat3 signaling and a dependency on this cytokine and transcription factor for migration, invasion and tumorigenesis.

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Ras transformation uncouples the kinesin-coordinated cellular nutrient response.

Publications

Ras transformation uncouples the kinesin-coordinated cellular nutrient response.

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