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.