WASp and WAVE Proteins: From Structure, Through Function, to Clinical Aspects

Abstract

The protein kinase C-theta (PKCθ) isoform is a member of the calcium-independent novel PKC subfamily of serine/threonine kinases. It is an essential regulatory enzyme in mature T lymphocytes, where it plays a key role in coupling the activated TCR and the CD28 costimulatory receptor to their downstream signaling pathways. TCR/ CD28 engagement induces the translocation of PKCθ to the center of the immunological synapse where it undergoes posttranslational modifications and becomes fully active. The activated PKCθ then initiates signaling pathways leading to the activation of transcription factors, including NF-κB, AP-1 and NF-AT that are essential for the survival, activation and differentiation of T cells. While PKCθ ablation was found to impair a wide range of in vitro responses of T cells, in vivo studies in Prkcq -/mice revealed that distinct T cell subpopulations differ in their requirements for PKCθ and that PKCθ has a selective role in different immune responses. Thus, PKCθ participates in cellular mechanisms leading to excessive inflammatory responses, autoimmunity, and graft vs host (GvH) disease, but is dispensable for beneficial immune responses against viruses and during graft vs leukemia responses. These studies suggest that PKCθ may serve as a potential drug target for catalytic and allosteric inhibitors in selected T cell-mediated diseases, and that fine-tuning of PKCθ-dependent functions may help prevent autoimmunity and GvH, without impairing the ability of T cells to eradicate viral-infected and transformed cells. PKCθPKCθ is a member of the novel PKC subfamily, initially isolated from T cells, skeletal muscle and platelets [25][26][27]. Additional studies demonstrated that PKCθ exhibits a relatively restricted pattern of expression, with high levels in T lymphocytes [23,25], platelets [27][28][29][30] Citation: Isakov N (2012) PKCθ is a Key Regulator of T-cell Behavior and a Drug Target for T cell-mediated Diseases.

Actin Retrograde Flow Regulated by the Wiskott–Aldrich Syndrome Protein Drives the Natural Killer Cell Response

“…WASp is associated with a multi-protein complex together with myosin IIA at the NKIS. WASp has been extensively studied to date, including its role as a scaffold protein for assembly of effective signaling complexes, and its function as an important regulator for effective migration, phagocytosis and immune synapse formation in both myeloid and lymphoid immune cells [ 10 , 55 ]. In the current study, we reveal the role of WASp in modulating ARF velocity downstream to receptor engagement, thereby regulating SHP-1 conformational structure, and consequently, its enzymatic activity.…”

“…Over the last decade, the actin cytoskeleton was shown to play a central role in NKIS formation and maturation, and as a mechanosensor for NK cell responses to mechanical stimuli, beyond its critical role as a scaffold for signaling molecules [ 9 ]. One such molecule, the Wiskott-Aldrich syndrome protein (WASp), activates actin polymerization by serving as a nucleation promoting factor (NPF) for the Arp2/3 complex, a macromolecular machinery that nucleates branched actin filaments in response to cellular signals [ 10 , 11 , 12 ]. Upon NK cell activation, WASp forms a multi-protein complex with WASp-interacting protein (WIP), actin, and myosin, and these associations are abrogated during NK cell inhibition [ 13 , 14 , 15 , 16 ].…”

WAVE-2 and Its Role in LRRK2 Mediated Neuroinflammation

“…The Wiskott-Aldrich syndrome protein (WASP) and WASP-family verprolinhomologous protein (WAVE) have known to be the fundamental regulator of actin cytoskeleton (Pollitt & Insall, 2009;Reicher et al, 2012;Joseph et al, 2017). The first human WAVE protein was identified independently by two groups as a WASP-like molecule and was named WAVE and SCAR respectively (Miki, Suetsugu & Takenawa, 1998;Machesky & Insall, 1998).…”

“…WAVE proteins exist as a part of a pentameric protein complex called "WAVE Regulatory Complex or WRC" (Pollitt & Insall, 2009). This complex consists of two WASP proteins; hematopoietic WASP and neural or N-WASP and three WAVE proteins; WAVE1, WAVE2, and WAVE3 (Reicher et al, 2012). All five WAVE family proteins are required for the stability of WRC (Noah Joseph et al, 2017).…”

“…WAVE2 is a central regulator of F-actin polymerization(Pollitt and Insall., 2009). Interestingly, WAVE 2 deficiency is embryonically lethal, as WAVE2 deficient mice die at embryonic day 10 due to hemorrhage caused by aberrant platelets(Reicher et al, 2012).…”