Browsing by Author "Kaur, Harjot"

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    Mechanisms and consequences of regulating neurabin and spinophilin's interaction with the tumor suppressor protein p140CAP
    (2017) Kaur, Harjot; Baucum, A.J.
    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.
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    Mechanisms Regulating the Association of Protein Phosphatase 1 with Spinophilin and Neurabin
    (American Chemical Society, 2018-11-21) Edler, Michael C.; Salek, Asma B.; Watkins, Darryl S.; Kaur, Harjot; Morris, Cameron W.; Yamamoto, Bryan K.; Baucum, Anthony J., II; Biology, School of Science
    Protein phosphorylation is a key mediator of signal transduction, allowing for dynamic regulation of substrate activity. Whereas protein kinases obtain substrate specificity by targeting specific amino acid sequences, serine/threonine phosphatase catalytic subunits are much more promiscuous in their ability to dephosphorylate substrates. To obtain substrate specificity, serine/threonine phosphatases utilize targeting proteins to regulate phosphatase subcellular localization and catalytic activity. Spinophilin and its homologue neurabin are two of the most abundant dendritic spine-localized protein phosphatase 1 (PP1) targeting proteins. The association between spinophilin and PP1 is increased in the striatum of animal models of Parkinson's disease (PD). However, mechanisms that regulate the association of spinophilin and neurabin with PP1 are unclear. Here, we report that the association between spinophilin and PP1α or PP1γ1 was increased by CDK5 expression and activation in a heterologous cell system. This increased association is at least partially due to phosphorylation of PP1. Conversely, CDK5 expression and activation decreased the association of PP1 with neurabin. As with dopamine depletion, methamphetamine (METH) abuse causes persistent alterations in dopamine signaling which influence striatal medium spiny neuron function and biochemistry. Moreover, both METH toxicity and dopamine depletion are associated with deficits in motor control and motor learning. Pathologically, we observed a decreased association of spinophilin with PP1 in rat striatum evaluated one month following a binge METH paradigm. Behaviorally, we found that loss of spinophilin recapitulates rotarod pathology previously observed in dopamine-depleted and METH-treated animals. Together, these data have implications in multiple disease states associated with altered dopamine signaling such as PD and psychostimulant drug abuse and delineate a novel mechanism by which PP1 interactions with spinophilin and neurabin may be differentially regulated.