IQGAPs choreograph cellular signaling from the membrane to the nucleus

Abstract

Since its discovery in 1994, cellular functions for the scaffold protein IQGAP1 have expanded immensely. Over 100 unique IQGAP1 interacting proteins have been identified, implicating IQGAP1 as a critical integrator of cellular signaling pathways. Initial research established functions for IQGAP1 in cell-cell adhesion, cell migration, and cell signaling. Recent studies have revealed additional IQGAP1 binding partners, expanding the biological roles of IQGAP1. These include crosstalk between signaling cascades, regulation of nuclear function, and Wnt pathway potentiation. Investigation of the IQGAP2 and IQGAP3 homologues demonstrate unique functions, some of which differ from those of IQGAP1. Summarized here are recent observations that enhance our understanding of IQGAP proteins in integrating diverse signaling pathways.

The IQD Family of Calmodulin-Binding Proteins Links Calcium Signaling to Microtubules, Membrane Subdomains, and the Nucleus

“…Stimulus-specific activation of Ca 2+ signaling pathways may specify and fine-tune the IQD affinity to MTs, the PM, and other interactors, such as IQD1-binding KLCR1 . Alternatively, as reported for fungal and mammalian IQGAP scaffold proteins, which orchestrate cellular signaling from the PM to the nucleus (Shannon, 2012;Smith et al, 2015), IQDs may act as reservoirs for CaM/CMLs. In that case, IQD proteins sequester apo-CaM/CMLs at specific subcellular sites, which upon Ca 2+ sensing and loading are transferred to targets regulated by holo-CaM/ CMLs, or vice versa.…”

“…For example, in yeast and animals, Ras GTPase-activatinglike protein IQGAP (IQGAP) scaffold proteins, which recruit CaM via IQ motifs and feature a domain related to GTPase-activating proteins, are key regulators of the cytoskeleton (Shannon, 2012). IQGAPs contribute to the regulation of cell-to-cell contact and coordinate intracellular signaling from membranes to the nucleus (Smith et al, 2015). However, plant genomes do not encode IQGAPs, and the mechanisms of Ca 2+ -mediated cytoskeletal organization are largely elusive (Hepler, 1992(Hepler, , 2005Wang et al, 2011).…”

IQGAP scaffold proteins are the multifunctional regulators of cellular signaling and malignant transformation

“…Гиперэкспрессия скаф-фолд-белка NEDD9 вызывает значительное повы-шение способности опухолевых клеток к миграции и инвазии, нарушениям клеточного цикла и цитокине-за [3]. Многообещающими объектами для исследова-ния в этом направлении представляются белки семей-ства IQGAP (белки-активаторы ГТФаз, содержащие IQ-мотивы, IQ Motif Containing GTPase Activating Protein) [4]. Данный обзор посвящен детальному рассмо-трению строения и функций этих белков, а также их связи с развитием онкологических заболеваний.…”

“…Белки семейства IQGAP экспрессируются у всех эука-риот -от Saccharomyces cerevisiae до человека [4]. У мле-копитающих описано 3 представителя этого семейства: IQGAP1 (хромосома 15, локус q26.1), IQGAP2 (хромо-сома 5, локус q13.3) и IQGAP3 (хромосома 1, локус q21.3) с аналогичным доменным строением, но различными паттернами тканеспецифической экспрессии, внутри-клеточной локализацией и функциями [5,6].…”

“…Доменная структура белков семейства IQGAP Белки семейства IQGAP -большие цитоплазма-тические скаффолд-белки массой 180-190 кДа [4]. Аминокислотные последовательности IQGAP2 и IQGAP3 идентичны IQGAP1 на 62 и 59 % соответственно [7].…”