Ras regulates kinesin 13 family members to control cell migration pathways in transformed human bronchial epithelial cells

Zaganjor, Elma; Osborne, Jihan K.; Weil, Lauren M.; Díaz-Martínez, Laura A.; Gonzales, Joshua X.; Singel, Stina Mui; Larsen, Jill E.; Girard, Luc; Minna, John D.; Cobb, Melanie H.

doi:10.1038/onc.2013.486

Cited by 31 publications

(35 citation statements)

References 56 publications

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“…We recently found that KIF2A and the closely related kinesin KIF2C are both up-regulated in many cancers and that their persistent expression is supported by oncogenic K-Ras and ERK1/2 (19). As previously found in HeLa and 293 cells, depletion of KIF2A from HBEC3KT prevented typical lysosomal organization, and mTOR also remained diffuse and less well-localized with lysosomes ( Fig.…”

Section: Significancesupporting

confidence: 51%

“…mRNAs encoding KIF2C and, to a lesser extent, KIF2A are decreased in both HBEC3KT and HBEC3KTRL53 by extended exposure to PD0325901, which inhibits the enzymes MEK1 and MEK2 that activate ERK1/2 (19). These and other studies indicated that ERK1/2 stimulate KIF2A/C expression.…”

Section: Inhibition Of the Erk1/2 Pathway Alters Lysosome Positioningmentioning

confidence: 56%

“…Therefore, we explored the possibility that ERK1/2 may also influence organelle organization in immortalized cells through their ability to control the expression of proteins that alter microtubule dynamics including these kinesins. We inhibited ERK1/2 activation by exposure of cells to the MEK inhibitor PD0325901 briefly or for up to 2 d. We showed previously that serum can stimulate ERK1/2 immediately after washing out PD0325901 even if cells have been treated with the inhibitor for 2 d (19). In HBEC3KT, prolonged blockade of the ERK pathway with the MEK inhibitor had significant effects on mTOR and LAMP2 localizations, causing dispersal of both ( Fig.…”

Section: Inhibition Of the Erk1/2 Pathway Alters Lysosome Positioningmentioning

confidence: 99%

“…We examined the characteristics of a nontumor human bronchial epithelial cell line (HBEC) that was immortalized by expression of cyclin-dependent kinase 4 (CDK4) and telomerase (hTERT), yielding HBEC3KT (number distinguishes different cell donors) as described (20). These cells maintain epithelial morphology and express E-cadherin but not N-cadherin (19). We compared the behavior of this immortalized untransformed cell line to an isogenic non-small cell lung cancer (NSCLC) model that was generated by introducing mutant K-Ras and a stable knockdown of p53 to yield HBEC3KTRL53 (21,22).…”

Section: Kif2a and Kif2c Are Required For The Amino Acid-dependentmentioning

confidence: 99%

“…We recently determined that expression of KIF2C and KIF2A is up-regulated by the Ras-ERK pathway (19). Therefore, we asked whether ERK1/2 and these kinesins are required to maintain lysosomal organization in immortalized human bronchial epithelial cells (HBECs) and also whether the elevated expression of KIF2C and KIF2A accounts for the nutrient insensitivity of lysosomal positioning and mTORC1 activity in a mutant K-Ras-dependent cancer and cancer model.…”

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confidence: 99%

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Ras transformation uncouples the kinesin-coordinated cellular nutrient response

Zaganjor¹,

Weil²,

Gonzales³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Significancesupporting

confidence: 51%

Section: Inhibition Of the Erk1/2 Pathway Alters Lysosome Positioningmentioning

confidence: 56%

Section: Inhibition Of the Erk1/2 Pathway Alters Lysosome Positioningmentioning

confidence: 99%

Section: Kif2a and Kif2c Are Required For The Amino Acid-dependentmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Ras transformation uncouples the kinesin-coordinated cellular nutrient response

Zaganjor¹,

Weil²,

Gonzales³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Overexpression of KIF20A confers malignant phenotype of lung adenocarcinoma by promoting cell proliferation and inhibiting apoptosis

Zhao

Zhou

et al. 2018

Cancer Medicine

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Increasing studies showed that kinesin family member 20A (KIF20A) was overexpessed in several types of cancer, and its overexpression correlated with the oncogenesis and prognosis of cancers. However, little is known about the role of KIF20A in lung adenocarcinoma (LUAD). In this study, we employed the bioinformatics analysis to identify the upregulation of KIF20A in LUAD, then verified the results in human tumor specimens and LUAD cell lines. Compared with normal lung tissues, a ubiquitous upregulation of KIF20A was observed in LUAD tissues by immunohistochemistry (IHC) as well as TCGA analysis. Higher expression of KIF20A was significantly associated with more advanced clinicopathological features and shorter overall survival (OS). Moreover, multivariate Cox regression analysis revealed that KIF20A was an independent prognostic factor for OS. The expression of KIF20A was significantly elevated in LUAD cell lines. After silencing KIF20A, lung cancer cell cycle arrested in G1 phase and apoptosis increased. The same results were observed in vivo. Thus, our study demonstrated that KIF20A might confer malignant phenotype to LUAD by regulating cell proliferation and apoptosis, providing a new potential biomarker for clinical treatment of LUAD.

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ILEI is an important intermediate participating in the formation of TGF‐β1–induced renal tubular EMT

Zhao

Luo

Fan

et al. 2018

Cell Biochemistry & Function

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There is no study reporting the effect of ILEI in renal EMTs. In this research, we examined the role and mechanism of ILEI in EMT using tubular epithelial cell; we found that ILEI participated in renal tubular EMT, and overexpression of ILEI can not only induce EMT of HK-2 cells independently but also enhance EMT in response to TGF-β1. Meanwhile, we found ILEI small interfering RNA blocked the EMT induced by TGF-β1, and ILEI participates in the EMT caused by TGF-β1 via ERK and Akt signalling pathways. We hoped to provide new ideas in further study on the prevention and treatment of fibrotic kidney diseases.

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Ras regulates kinesin 13 family members to control cell migration pathways in transformed human bronchial epithelial cells

Cited by 31 publications

References 56 publications

Ras transformation uncouples the kinesin-coordinated cellular nutrient response

Ras transformation uncouples the kinesin-coordinated cellular nutrient response

Overexpression of KIF20A confers malignant phenotype of lung adenocarcinoma by promoting cell proliferation and inhibiting apoptosis

ILEI is an important intermediate participating in the formation of TGF‐β1–induced renal tubular EMT

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