title: 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.
authors.affiliation: Department of Pharmacology and.
authors.forename: Elma
authors.initials: E
authors.lastname: Zaganjor
authors.affiliation: Department of Pharmacology and.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Weil
authors.affiliation: Department of Pharmacology and.
authors.forename: Joshua X
authors.initials: JX
authors.lastname: Gonzales
authors.affiliation: Department of Pharmacology andHamon Cancer Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Department of Pharmacology and melanie.cobb@utsouthwestern.edu.
authors.forename: Melanie H
authors.initials: MH
authors.lastname: Cobb
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D001343:Autophagy; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology*; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D034741:RNA, Small Interfering / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000596:Amino Acids; C509805:KIF2A protein, human; C091489:KIF2C protein, human; C117307:KRAS protein, human; D046912:Multiprotein Complexes; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D016547:Kinesins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins