β PAK-interacting exchange factor may regulate actin cytoskeleton through interaction with actin

Lee, Chan Soo; Kim, Kyung Yong; Im, Jae Bin; Choi, Jae Woon; Kim, Hyong Kyu; Park, Jeong‐Soo; Shin, Eun Young; Kim, Seung Ryul; Kim, Eung Gook

doi:10.1038/emm.2004.75

Cited by 4 publications

(3 citation statements)

References 16 publications

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“…Anti-phospho-threonine, and Alexa Fluor 488 and 594–conjugated secondary antibodies were purchased from Invitrogen (Carlsbad, CA, USA). The anti-βPIX monoclonal antibody was raised against amino acids 439–648 of βPIX [17]. Blebbistatin (BBS) was obtained from Tocris Bioscience (Minneapolis, MN, USA).…”

Section: Methodsmentioning

confidence: 99%

Non-Muscle Myosin II Regulates Neuronal Actin Dynamics by Interacting with Guanine Nucleotide Exchange Factors

et al. 2014

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BackgroundNon-muscle myosin II (NM II) regulates a wide range of cellular functions, including neuronal differentiation, which requires precise spatio-temporal activation of Rho GTPases. The molecular mechanism underlying the NM II-mediated activation of Rho GTPases is poorly understood. The present study explored the possibility that NM II regulates neuronal differentiation, particularly morphological changes in growth cones and the distal axon, through guanine nucleotide exchange factors (GEFs) of the Dbl family.Principal FindingsNM II colocalized with GEFs, such as βPIX, kalirin and intersectin, in growth cones. Inactivation of NM II by blebbistatin (BBS) led to the increased formation of short and thick filopodial actin structures at the periphery of growth cones. In line with these observations, FRET analysis revealed enhanced Cdc42 activity in BBS-treated growth cones. BBS treatment also induced aberrant targeting of various GEFs to the distal axon where GEFs were seldom observed under physiological conditions. As a result, numerous protrusions and branches were generated on the shaft of the distal axon. The disruption of the NM II–GEF interactions by overexpression of the DH domains of βPIX or Tiam1, or by βPIX depletion with specific siRNAs inhibited growth cone formation and induced slender axons concomitant with multiple branches in cultured hippocampal neurons. Finally, stimulation with nerve growth factor induced transient dissociation of the NM II–GEF complex, which was closely correlated with the kinetics of Cdc42 and Rac1 activation.ConclusionOur results suggest that NM II maintains proper morphology of neuronal growth cones and the distal axon by regulating actin dynamics through the GEF–Rho GTPase signaling pathway.

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Section: Methodsmentioning

confidence: 99%

Non-Muscle Myosin II Regulates Neuronal Actin Dynamics by Interacting with Guanine Nucleotide Exchange Factors

et al. 2014

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“…Next, we aimed to determine how core fucosylation of CD123 mediates sensitivity to CD123-DART treatment. We applied the Scramble and FUT8 KO cells in FACS assays with a widely reported anti-CD123 antibody 6H6 (35). No significant difference was found between the two groups, indicating that loss of core fucosylation did not alter CD123's surface expression ( Figure 4A).…”

Section: Core Fucosylation Of Cd123 Is Required For Efficient Bindingmentioning

confidence: 96%

A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy

Liu¹,

Grantham²,

Landry³

et al. 2021

Cancer Immunology Research

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CD3-bispecific antibodies represent an important therapeutic strategy in oncology. These molecules work by redirecting cytotoxic T cells to antigen-bearing tumor cells. Although CD3-bispecific antibodies have been developed for several clinical indications, cases of cancer-derived resistance are an emerging limitation to the more generalized application of these molecules. Here, we devised whole-genome CRISPR screens to identify cancer resistance mechanisms to CD3-bispecific antibodies across multiple targets and cancer types. By validating the screen hits, we found that deficiency in IFNγ signaling has a prominent role in cancer resistance. IFNγ functioned by stimulating the expression of T-cell killing–related molecules in a cell type–specific manner. By assessing resistance to the clinical CD3-bispecific antibody flotetuzumab, we identified core fucosylation as a critical pathway to regulate flotetuzumab binding to the CD123 antigen. Disruption of this pathway resulted in significant resistance to flotetuzumab treatment. Proper fucosylation of CD123 was required for its normal biological functions. In order to treat the resistance associated with fucosylation loss, flotetuzumab in combination with an alternative targeting CD3-bispecific antibody demonstrated superior efficacy. Together, our study reveals multiple mechanisms that can be targeted to enhance the clinical potential of current and future T-cell–engaging CD3-bispecific antibody therapies.

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“…Mouse anti-βPIX mAb (C-B7) detects PIX at both centrosomes and focal adhesions and was a kind gift from Dr. E.G. Kim (Lee et al, 2004). Purified rabbit anti-PAK2 polyclonal antibody has been described previously (Teo et al, 1995).…”

Section: Antibodiesmentioning

confidence: 99%

The GIT-Associated Kinase PAK Targets to the Centrosome and Regulates Aurora-A

et al. 2005

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Previously, we showed PAK-PIX-GIT targets and regulates focal adhesions; here, we uncover a different function for the complex at the centrosome. Active PAK1 is particularly evident in mitosis and phosphorylates the centrosomal adaptor GIT1 on serine 517. Interestingly, direct centrosome targeting activates the kinase via a process not requiring Rho GTPases; excision of the centrosome prevents this activation. Once activated, PAK1 dissociates from PIX/GIT but can bind to and phosphorylate the important centrosomal kinase Aurora-A. PAK1 promotes phosphorylation of Aurora-A on Thr288 and Ser342, which are key sites for kinase activation in mitosis. In vivo PAK activation causes an accumulation of activated Aurora-A; conversely, when betaPIX is depleted or PAK is inhibited, there is a delay in centrosome maturation. These observations may underlie reported effects of active PAK on cells, including histone H3 phosphorylation, alterations in centrosome number, and progression through mitosis.

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β PAK-interacting exchange factor may regulate actin cytoskeleton through interaction with actin

Abstract: A bstract p21-activated kin ase (P A K )-in teracting exch ange facto r (P IX)

Cited by 4 publications

References 16 publications

Non-Muscle Myosin II Regulates Neuronal Actin Dynamics by Interacting with Guanine Nucleotide Exchange Factors

Non-Muscle Myosin II Regulates Neuronal Actin Dynamics by Interacting with Guanine Nucleotide Exchange Factors

A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy

The GIT-Associated Kinase PAK Targets to the Centrosome and Regulates Aurora-A

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