Mechanisms and consequences of regulating neurabin and spinophilin's interaction with the tumor suppressor protein p140CAP

Abstract

Glioblastoma is the most aggressive type of brain cancer with very poor prognosis. Due to the lack of understanding of underlying mechanisms, there are no anti-invasive clinical therapeutics available. SRC terminal kinase (SRC) is a tumorigenic protein that is highly expressed in glioblastoma samples. SRC inhibitor kinase 1 (SRCIN1), also known as p140Cap is a negative regulator of SRC. Silencing SRCIN1 results in increased tumor invasion. Our lab has discovered two novel scaffolding proteins Spinophilin (Spn) and neurabin (Nrb) that bind to SRCIN1. They may play a role in regulating SRCIN1 activity, as well as its downstream effects that ultimately decrease SRC’s tumorigenic activity. Spn and Nrb are two scaffolding proteins that are heavily expressed in the central nervous system. Spn knockout mice develop more tumors, indicating that Spn acts as a tumor suppressor protein, although the mechanisms of Spn’s anti-tumor properties are not well understood. Spn and Nrb are PP1 targeting proteins that target PP1 to other substrates, resulting in dephosphorylation and alteration of function. We found that PP1 increases Spn association with SRCIN1, but decreases Nrb association with SRCIN1, indicating that the two proteins might have opposite effects to balance the activity of p140Cap. We also found that cyclin-dependent kinase 5 (CDK5) phosphorylates and regulates the association of these scaffolding proteins with the tumor suppressor protein, p140Cap. Understanding these mechanisms provides insight into new therapeutic targets that may ultimately decrease SRC activity and its tumorigenic and invasive properties.