IQGAP1 is a phosphoinositide effector and kinase scaffold

Choi, Sungyeol; Anderson, Richard A.

doi:10.1016/j.jbior.2015.10.004

Cited by 38 publications

(33 citation statements)

References 75 publications

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“…However, we managed to find some clues of this: (i) ORP2 was found to physically interact with IQGAP1 [35], a protein acting as a scaffold for phosphoinositide kinases [43] in the cascade that eventually produces PI3,4,5P 3 , a key messenger in the PI3K/Akt signaling pathway and (ii) ORP2 was found to physically interact with Cdc37 and Hsp90 [27], which form a chaperone complex required for Akt activity [44]. The above results suggested that ORP2 not only regulates the cellular TG metabolism, but has more global impacts on energy metabolism.…”

Section: Function Of Orp2 In the Carbohydrate Metabolism Of Hepatoma mentioning

confidence: 99%

OSBP-related protein 2 (ORP2): Unraveling its functions in cellular lipid/carbohydrate metabolism, signaling and F-actin regulation

Olkkonen

Koponen

Arora

2019

The Journal of Steroid Biochemistry and Molecular Biology

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Oxysterol-binding protein (OSBP)-related proteins (ORPs) constitute a family of intracellular lipid-binding/ transport proteins (LTPs) in eukaryotes. They typically have a modular structure comprising a lipid-binding domain and membrane targeting determinants, being thus suited for function at membrane contact sites. Among the mammalian ORPs, ORP2/OSBPL2 is the only member that only exists as a 'short' variant lacking a membrane-targeting pleckstrin homology domain. ORP2 is expressed ubiquitously and has been assigned a multitude of functions. Its OSBP-related domain binds cholesterol, oxysterols, and phosphoinositides, and its overexpression enhances cellular cholesterol efflux. Consistently, the latest observations suggest a function of ORP2 in cholesterol transport to the plasma membrane (PM) in exchange for phosphatidylinositol 4,5-bisphosphate (PI4,5P 2), with significant impacts on the concentrations of PM cholesterol and PI4,5P 2. On the other hand, ORP2 localizes at the surface of cytoplasmic lipid droplets (LDs) and at endoplasmic-reticulum-LD contact sites, and its depletion modifies cellular triglyceride (TG) metabolism. Study in an adrenocortical cell line further suggested a function of ORP2 in the synthesis of steroid hormones. Our recent knockout of ORP2 in human hepatoma cells revealed its function in hepatocellular PI3K/Akt signaling, glucose and triglyceride metabolism, as well as in actin cytoskeletal regulation, cell adhesion, migration and proliferation. ORP2 was shown to interact physically with F-actin regulators such as DIAPH1, ARHGAP12, SEPT9 and MLC12, as well as with IQGAP1 and the Cdc37-Hsp90 chaperone complex controlling the activity of Akt. Interestingly, mutations in OSBPL2 encoding ORP2 are associated with autosomal dominant non-syndromic hearing loss, and the protein was found to localize in cochlear hair cell stereocilia. The functions assigned to ORP2 suggest that this protein, in concert with other LTPs, controls the subcellular distribution of cholesterol in various cell types and steroid hormone synthesis in adrenocortical cells. However, it also impacts cellular TG and carbohydrate metabolism and F-actin-dependent functions, revealing a bewildering spectrum of activities.

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Section: Function Of Orp2 In the Carbohydrate Metabolism Of Hepatoma mentioning

confidence: 99%

OSBP-related protein 2 (ORP2): Unraveling its functions in cellular lipid/carbohydrate metabolism, signaling and F-actin regulation

Olkkonen

Koponen

Arora

2019

The Journal of Steroid Biochemistry and Molecular Biology

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“…The plasma membrane recruitment of IQGAP1 is critical for its regulation of cytoskeletal reorganization and migration (10)(11)(12). IQGAP1 was reported to bind to PI(4,5)P2, and this binding is required for the activation but not the membrane recruitment of IQGAP1 (46,52). We find that PA binds to the C terminus of IQGAP1 at a site different from the PI(4,5)P2-binding site (Fig.…”

Section: Discussionmentioning

confidence: 66%

Phosphatidic acid generated by PLD2 promotes the plasma membrane recruitment of IQGAP1 and neointima formation

et al. 2019

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Very little is known about how lipid signaling regulates intima hyperplasia after vascular injury. Herein, we report that deletion and pharmacological inhibition of phospholipase D (PLD)2, which generates the signaling lipid phosphatidic acid (PA), reduced neointimal formation in the mouse carotid artery ligation model. PLD2 deficiency inhibits migration of vascular smooth muscle cells (VSMCs) into the intima in mice as well as migration and formation of membrane ruffles in primary VSMCs. PA specifically binds to the IQ motif–containing guanosine triphosphatase–activating protein 1 (IQGAP1) scaffold protein. The binding between PA and IQGAP is required for the plasma membrane recruitment of IQGAP1. Similar to PLD2 inhibition, knockdown of IQGAP1 blocks ruffle formation and migration in VSMCs, which are rescued by expression of the exogenous IQGAP1 but not the PA binding–deficient mutant. These data reveal that the PLD2‐PA‐IQGAP1 pathway plays an important role in VSMC migration and injury‐induced vascular remodeling, and implicate PLD2 as a candidate target for therapeutic interventions.—Wang, Z., Cai, M., Tay, L. W. R., Zhang, F., Wu, P., Huynh, A., Cao, X., Di Paolo, G., Peng, J., Milewicz, D. M., Du, G. Phosphatidic acid generated by PLD2 promotes the plasma membrane recruitment of IQGAP1 and neointima formation. FASEB J. 33, 6713–6725 (2019). http://www.fasebj.org

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“…PAK6 may further influence carcinogenesis and prostate cancer progression through diverse signal transduction pathways including protein phosphatase 1B (PP1B) and IQGAP1, both of which are PAK6 interacting partners (Kaur et al, 2008;Fram et al, 2014). IQGAP1 plays a critical role in cell adhesion and coordinates multiple signaling pathways in many cell types (Choi, Anderson, 2016;Abel et al, 2015).…”

Section: Prostate Cancermentioning

confidence: 99%

PAK6: a potential anti-cancer target

Gong

Pei

2020

Braz. J. Pharm. Sci.

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p21-activated kinase 6 (PAK6) is a member of the PAK family of serine/threonine kinases that are known effectors of Rho GTPases Cdc42 and Rac. PAKs regulate a large number of complex cellular mechanisms, including cell motility, morphology, and tumor development. PAK6, initially cloned as an interacting partner of the androgen receptor (AR), is associated with an array of cellular processes implicated in tumor progression. However, the full biological implications of PAK6 activity during cancer remain poorly understood. In this review, we assess our current understanding of the physiological roles of classical PAK6 functionality in mammals, in addition to its emerging role in tumorigenesis.

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IQGAP1 is a phosphoinositide effector and kinase scaffold

Cited by 38 publications

References 75 publications

OSBP-related protein 2 (ORP2): Unraveling its functions in cellular lipid/carbohydrate metabolism, signaling and F-actin regulation

OSBP-related protein 2 (ORP2): Unraveling its functions in cellular lipid/carbohydrate metabolism, signaling and F-actin regulation

Phosphatidic acid generated by PLD2 promotes the plasma membrane recruitment of IQGAP1 and neointima formation

PAK6: a potential anti-cancer target

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