A Reassessment of Phosphatidylinositol Transfer Protein Alpha's Growth Factor Signaling Role

Abstract

In mammals, the START‐like phosphatidylinositol transfer proteins (PITPs) remain an understudied group of proteins implicated in human health and disease. Phosphatidylinositol transfer protein alpha (PITPa) is linked to human epidermal growth factor receptor (HER2)‐positive metastatic breast cancer drug resistance, and muscular dystrophy, but its precise mechanism of action is unclear. Current dogma states that PITPa is essential for growth factor signaling through the epidermal growth factor (EGFR) and netrin signaling pathways, but little data has emerged supporting these claims. Data from our laboratory, from multiple experimental systems, strongly dispute PITPa requirement in these pathways. Strikingly, mouse and human cell lines lacking PITPa sense and chemotax towards EGF, and signaling responses downstream of EGFR‐stimulation are unimpaired, including phosphatidylinositol (3,4,5)P3 generation, and phosphorylation of protein kinase B (Akt). Surprisingly, lack of PITPa in human cells results in potentiation of Akt phosphorylation (threonine 308) following EGFR stimulation, indicating that contrary to current thinking, PITPa may actually repress this pathway. The dispensability of PITPa for EGF‐signaling explains the remarkable absence of EGF‐signaling associated phenotypes in PITPa nullizygous (Pitpa0/0) mice. We have previously reported that Pitpa0/0 animals exhibit a complex phenotype including spinocerebellar neurodegeneration characterized by gliosis and neuronal apoptosis of cerebellum, and hindbrain, and that neuronal specific eviction of embryonic PITPa and PITPb results in progeny born lacking a forebrain. Axon guidance and mouse forebrain development require netrin‐1 signaling through the netrin receptor (DCC), a process reported to require PITPa. We demonstrate that while compromise of netrin‐signaling results in structural brain derangements, these defects do not result from absence of PITPa. Furthermore, we fail to reproduce the previously reported physical interaction between the netrin receptor (DCC) and PITPa. In light of our findings the ‘essential’ role of PITPa in growth factor signaling must be reevaluated.Support or Funding InformationThis work was supported by the Robert A. Welch Foundation (BE0017), and a National Institutes of Health grant (GM44530) awarded to Vytas A. BankaitisThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.