title: Paxillin mutations affect focal adhesions and lead to altered mitochondrial dynamics: relevance to lung cancer.
abstract: Cytoskeletal and focal adhesion abnormalities are observed in several types of cancer, including lung cancer. We have previously reported that paxillin (PXN) was mutated, amplified, and overexpressed in a significant number of lung cancer patient samples, that PXN protein was upregulated in more advanced stages of lung cancer compared with lower stages, and that the PXN gene was also amplified in some pre-neoplastic lung lesions. Among the mutations investigated, we previously found that PXN variant A127T in lung cancer cells enhanced cell proliferation and focal adhesion formation and colocalized with the anti-apoptotic protein B Cell Lymphoma 2 (BCL-2), which is known to localize to the mitochondria, among other sites. To further explore the effects of activating mutations of PXN on mitochondrial function, we cloned and expressed wild-type PXN and variants containing the most commonly occurring PXN mutations (P46S, P52L, G105D, A127T, P233L, T255I, D399N, E423K, P487L, and K506R) in a GFP-tagged vector using HEK-293 human embryonic kidney cells. Utilizing live-cell imaging to systematically study the effects of wild-type PXN vs. mutants, we created a model that recapitulates the salient features of the measured dynamics and conclude that compared with wild-type, some mutant clones confer enhanced focal adhesion and lamellipodia formation (A127T, P233L, and P487L) and some confer increased association with BCL-2, Dynamin-related Protein-1 (DRP-1), and Mitofusion-2 (MFN-2) proteins (P233L and D399N). Further, PXN mutants, through their interactions with BCL-2 and DRP-1, could regulate cisplatin drug resistance in human lung cancer cells. The data reported herein suggest that mutant PXN variants play a prominent role in mitochondrial dynamics with direct implications on lung cancer progression and hence, deserve further exploration as therapeutic targets.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawada
authors.forename: Rifat
authors.initials: R
authors.lastname: Hasina
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lennon
authors.forename: Vytautas P
authors.initials: VP
authors.lastname: Bindokas
authors.forename: Peter
authors.initials: P
authors.lastname: Usatyuk
authors.forename: Yi-Hung C
authors.initials: YH
authors.lastname: Tan
authors.forename: Soundararajan
authors.initials: S
authors.lastname: Krishnaswamy
authors.forename: Qudsia
authors.initials: Q
authors.lastname: Arif
authors.forename: George
authors.initials: G
authors.lastname: Carey
authors.forename: Robyn D
authors.initials: RD
authors.lastname: Hseu
authors.forename: Matthew
authors.initials: M
authors.lastname: Robinson
authors.forename: Maria
authors.initials: M
authors.lastname: Tretiakova
authors.forename: Toni M
authors.initials: TM
authors.lastname: Brand
authors.forename: Mari
authors.initials: M
authors.lastname: Iida
authors.forename: Mark K
authors.initials: MK
authors.lastname: Ferguson
authors.forename: Deric L
authors.initials: DL
authors.lastname: Wheeler
authors.forename: Aliya N
authors.initials: AN
authors.lastname: Husain
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Singleton
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
mesh_terms: D022001:Focal Adhesions / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000235:genetics*; D009154:Mutation; D051419:Paxillin / Q000235:genetics* / Q000378:metabolism
chemical_list: D051419:Paxillin
keywords: cell motility; fission; fusion; gene mutation; mitochondria; mitochondrial dynamics; paxillin