title: Significance of Trask protein interactions in brain metastatic cohorts of lung cancers.
abstract: A class of adhesion protein that occurs in the membrane with both extracellular and intracellular domain and play vital role in maintaining multicellularity is TRASK, also called CUB-domain containing protein1, CD318 (CDCP1). Specifically, in the current study, documented aggressive grades of lung cancers and distant metastatic tissues were examined for protein interactions of Trask and compared with lung cancer variants in situ. The intracellular domain of Trask has the ability to undergo tyrosine phosphorylation and thereafter undergo increased genomic expression, as well as interact with cytoskeletal proteins in the cell periphery and other local signal transduction machinery to induce invadopodia formation and distant metastasis. We incorporated proximity ligation assay to examine protein interactions of Trask in metastatic lung cancer tissues and compare with advanced and low-grade lung cancers restricted to the primary site of origins. Here, we provide direct evidence that activated Trask, which is a phosphorylated form, binds with cytoskeletal proteins actin and spectrin. These interactions were not seen in locally growing lung cancer and cancer in situ. These interactions may be responsible for invadopodia formation and breaking free from a multicellular environment. Functional studies demonstrated interaction between Trask and the STOCs Orai1 and Stim1. Calcium release from internal stores was highest in metastatic lung cancers, suggesting this mechanism as an initial stimulus for the cells to respond chaotically to external growth factor stimulation, especially in aggressive metastatic variants of lung cancers. Recently, inhibitors of STOCs have been identified, and preclinical evidence may be obtained whether these drugs may be of benefit in preventing the deadly consequences of lung cancer.
authors.affiliation: Department of Respiratory Medicine, Shaanxi Provincial People's Hospital, No. 256, Youyi West Road, Beilin District, Xi'an, 710068, Shaanxi, China, shanxiliwu@126.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Wu
authors.forename: Li-Qun
authors.initials: LQ
authors.lastname: Shang
authors.forename: Rui-Lin
authors.initials: RL
authors.lastname: Chen
authors.forename: Shu-Mei
authors.initials: SM
authors.lastname: Yang
authors.forename: Shui-Li
authors.initials: SL
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Sun
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D000951:Antigens, Neoplasm; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D000071740:ORAI1 Protein; D010766:Phosphorylation; D060066:Protein Interaction Maps; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology; D000071737:Stromal Interaction Molecule 1; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; C432044:CDCP1 protein, human; D015220:Calcium Channels; D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D019061:src-Family Kinases; D002118:Calcium