PAK signalling in neuronal physiology

Fayngerts

Proc. Natl. Acad. Sci. U.S.A.

et al. 2012

109

Phagocytosis and oxidative burst are two major effector arms of innate immunity. Although it is known that both are activated by Toll-like receptors (TLRs) and Rac GTPases, how their strengths are controlled in quiescent and TLR-activated cells is not clear. We report here that TIPE2 (TNFAIP8L2) serves as a negative regulator of innate immunity by linking TLRs to Rac. TLRs control the expression levels of TIPE2, which in turn dictates the strengths of phagocytosis and oxidative burst by binding to and blocking Rac GTPases. Consequently, TIPE2 knockout cells have enhanced phagocytic and bactericidal activities and TIPE2 knockout mice are resistant to bacterial infection. Thus, TIPE2 sets the strengths of phagocytosis and oxidative burst and may be targeted to effectively control infections.

Section: Tlr Stimulation and Bacterial Infection Markedly Diminish Tipe2mentioning

confidence: 67%

“…4D). Active Rac1 can induce the assembly of a filamentous (F)-actin structure through PAK-dependent and -independent signals (24). Because polymerization of F-actin can be induced by LPS, we next examined the effect of TIPE2 deficiency on LPS-induced F-actin polymerization.…”

Section: Tlr Stimulation and Bacterial Infection Markedly Diminish Tipe2mentioning

confidence: 99%

TIPE2 protein serves as a negative regulator of phagocytosis and oxidative burst during infection

Fayngerts

Proc. Natl. Acad. Sci. U.S.A.

et al. 2012

109

Proc. Natl. Acad. Sci. U.S.A.

“…Several upstream regulators of group I PAK kinases are wellcharacterized for their ability to affect neuronal structure and function (49). For instance, EphR-Ephrin signal transduction through PAKs plays a critical role in synaptogenesis and spine morphogenesis; activated EphRs bind to Kalirin, a neuronal exchange factor, which in turn stimulates Rac1-PAK-mediated signal transduction to trigger changes in dendritic spine morphology (10).…”

Section: Discussionmentioning

confidence: 99%

Regulation of AMPA receptor subunit GluA1 surface expression by PAK3 phosphorylation

Hussain

Thomas

Luo

et al. 2015

AMPA receptors (AMPARs) are the major excitatory receptors of the brain and are fundamental to synaptic plasticity, memory, and cognition. Dynamic recycling of AMPARs in neurons is regulated through several types of posttranslational modification, including phosphorylation. Here, we identify a previously unidentified signal transduction cascade that modulates phosphorylation of serine residue 863 (S863) in the GluA1 AMPAR subunit and controls surface trafficking of GluA1 in neurons. Activation of the EphR-Ephrin signal transduction pathway enhances S863 phosphorylation. Further, EphB2 can interact with Zizimin1, a guanine-nucleotide exchange factor that activates Cdc42 and stimulates S863 phosphorylation in neurons. Among the numerous targets downstream of Cdc42, we determined that the p21-activated kinase-3 (PAK3) phosphorylates S863 in vitro. Moreover, specific loss of PAK3 expression and pharmacological inhibition of PAK both disrupt activity-dependent phosphorylation of S863 in cortical neurons. EphB2, Cdc42, and PAKs are broadly capable of controlling dendritic spine formation and synaptic plasticity and are implicated in multiple cognitive disorders. Collectively, these data delineate a novel signal cascade regulating AMPAR trafficking that may contribute to the molecular mechanisms that govern learning and cognition.A MPARs (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) are the primary mediators of excitatory synaptic transmission in the brain (1). AMPARs are tetrameric ion channels that display distinct functional properties, based on which combinations of subunits, named GluA1-4, are coassembled to form receptor subtypes. Several studies demonstrate that aberrant AMPAR trafficking results in impaired memory and cognition and is associated with numerous neurological disorders (2). Dynamic control of AMPAR recycling to and from synapses is regulated through posttranslational modifications of receptor subunits and through specific interactions with accessory proteins, which in turn can be regulated by neuronal activity. For instance, patterned increases in neuronal activity can initiate signaling cascades that recruit AMPARs into the synaptic membrane and result in an overall strengthening of the synapse; this form of synaptic plasticity is called long-term potentiation (LTP). Conversely, stimulation protocols initiating postsynaptic membrane removal of AMPARs result in a weakening of the synapse and are known as long-term depression (LTD) (3). Several decades of research demonstrate that both LTP and LTD, widely considered the molecular correlates of learning and memory, can be explicitly modulated by the phosphorylation/ dephosphorylation state of AMPAR subunits (3).Members of the Rho GTPase family of proteins are molecular switches, transitioning between inactive/active states to control numerous physiological functions (4, 5). Canonical members include Rho, Rac1, and Cdc42, which regulate many cellular mechanisms, but particularly those involving actin cytoskeletal reorganization, suc...

Journal of Biological Chemistry

“…In their active forms, Rho GTPases stimulate downstream effectors to activate a diverse assortment of cellular mechanisms, including vesicular transport, microtubule dynamics, actin cytoskeleton remodeling, and cell cycle progression (25,26). Rac and Cdc42 signal through the p21-activated kinase (PAK) family of serine/threonine kinases and other effectors to modulate actin cytoskeletal dynamics, which are critical for axonal outgrowth, maintenance of dendritic spine, and neurite morphology (27,28). More specifically, PAK1 signals through ERK1/2 to regulate actin polymerization and lamellipodium stability (29).…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

Rac1 Protein Rescues Neurite Retraction Caused by G2019S Leucine-rich Repeat Kinase 2 (LRRK2)

Chan¹,

Citro²,

Cordy³

et al. 2011

109

111

Mutations in leucine-rich repeat kinase 2 (LRRK2) are currently the most common genetic cause of familial late-onset Parkinson disease, which is clinically indistinguishable from idiopathic disease. The most common pathological mutation in LRRK2, G2019S LRRK2, is known to cause neurite retraction. However, molecular mechanisms underlying regulation of neurite length by LRRK2 are unknown. Here, we demonstrate a novel interaction between LRRK2 and the Rho GTPase, Rac1, which plays a critical role in actin cytoskeleton remodeling necessary for the maintenance of neurite morphology. LRRK2 binds strongly to endogenous or expressed Rac1, while showing weak binding to Cdc42 and no binding to RhoA. Co-expression with LRRK2 increases Rac1 activity, as shown by increased binding to the p21-activated kinase, which modulates actin cytoskeletal dynamics. LRRK2 constructs carrying mutations that inactivate the kinase or GTPase activities do not activate Rac1. Interestingly, LRRK2 does not increase levels of membrane-bound Rac1 but dramatically changes the cellular localization of Rac1, causing polarization, which is augmented further when LRRK2 is co-expressed with constitutively active Rac1. Four different disease-related mutations in LRRK2 altered binding to Rac1, with the G2019S and R1441C LRRK2 mutations attenuating Rac1 binding and the Y1699C and I2020T LRRK2 mutations increasing binding. Co-expressing Rac1 in SH-SY5Y cells rescues the G2019S mutant phenotype of neurite retraction. We hypothesize that pathological mutations in LRRK2 attenuates activation of Rac1, causing disassembly of actin filaments, leading to neurite retraction. The interactions between LRRK2 and Rho GTPases provide a novel pathway through which LRRK2 might modulate cellular dynamics and contribute to the pathophysiology of Parkinson disease. Parkinson disease (PD)2 is the most common neurodegenerative movement disorder affecting nearly 1% of elderly over 65 years old. Idiopathic PD may result from a combination of factors including age, genetic predisposition, environmental toxins, and neuroinflammation (1, 2). Mutations in LRRK2 are the most common genetic cause of PD and also contribute to many sporadic cases of PD (3, 4). At least 20 mutations identified to date in LRRK2 cause autosomal-dominant PD, accounting for ϳ7% of all familial cases (4, 5). The missense mutation, G2019S, in the kinase domain of LRRK2 is by far the most common of the LRRK2 mutations associated with PD, and disease associated with the G2019S mutations is clinically indistinguishable from idiopathic disease (6).The Lrrk2 gene of 51 exons encodes a large, multidomain protein that includes an ankyrin repeat and leucine-rich repeat regions (6). The kinase domain of LRRK2 shares homology with receptor-interacting protein kinases and mixed lineage kinases (3, 7). LRRK2 also contains a Ras-of-complex (ROC) domain that exhibits GTPase activity (8,9). In between these two domains lies a C-terminal of Ras complex (COR) domain. Each of these domains is thought to be important for bindi...