Ras transformation uncouples the kinesin-coordinated cellular nutrient response

Elma Zaganjor, Lauren M. Weil, Joshua X. Gonzales, John D. Minna, Melanie H. Cobb

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)10568-10573
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number29
DOIs
StatePublished - Jul 22 2014

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Kinesin
Food
Lysosomes
Organizations
Microtubules
Epithelial Cells
Human Activities
Neoplasms
Cytoplasm
Up-Regulation
mechanistic target of rapamycin complex 1
Phenotype
Proteins

ASJC Scopus subject areas

  • General

Cite this

Ras transformation uncouples the kinesin-coordinated cellular nutrient response. / Zaganjor, Elma; Weil, Lauren M.; Gonzales, Joshua X.; Minna, John D.; Cobb, Melanie H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 29, 22.07.2014, p. 10568-10573.

Research output: Contribution to journalArticle

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