Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.4.4 (kinesin)
 5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ARF (ADP-ribosylation factor) family of small GTPases regulate intracellular membrane trafficking by cycling between an inactive GDP- and an active GTP-bound form. Among the six known mammalian ARFs (ARF1-ARF6), ARF6 is the least conserved and plays critical roles in membrane trafficking and cytoskeletal dynamics near the cell surface. Since ARFs have undetectable levels of intrinsic GTP binding and hydrolysis, they are totally dependent on extrinsic GEFs (guanine nucleotide-exchange factors) for GTP binding and GAPs (GTPase-activating proteins) for GTP hydrolysis. We have recently isolated a novel KIF (kinesin) motor protein (KIF13B) that binds to centaurin-alpha1, an ARF6GAP that binds to the second messenger PIP3 [PtdIns(3,4,5)P3]. KIFs transport intracellular vesicles and recognize their cargo by binding to proteins (receptors) localized on the surface of the cargo vesicles. Identification of centaurin-alpha1 as a KIF13B interactor suggests that KIF13B may transport ARF6 and/or PIP3 using centaurin-alpha1 as its receptor. This paper reviews the studies carried out to assess the interaction and regulation of centaurin-alpha1 by KIF13B.
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PMID:Centaurin-alpha1 and KIF13B kinesin motor protein interaction in ARF6 signalling. 1624 98

The JNK-interacting proteins, JIP3 and JIP4, are specific effectors of the small GTP-binding protein ARF6. The interaction of ARF6-GTP with the second leucine zipper (LZII) domains of JIP3/JIP4 regulates the binding of JIPs to kinesin-1 and dynactin. Here, we report the crystal structure of ARF6-GTP bound to the JIP4-LZII at 1.9 A resolution. The complex is a heterotetramer with dyad symmetry arranged in an ARF6-(JIP4)(2)-ARF6 configuration. Comparison of the ARF6-JIP4 interface with the equivalent region of ARF1 shows the structural basis of JIP4's specificity for ARF6. Using site-directed mutagenesis and surface plasmon resonance, we further show that non-conserved residues at the switch region borders are the key structural determinants of JIP4 specificity. A structure-derived model of the association of the ARF6-JIP3/JIP4 complex with membranes shows that the JIP4-LZII coiled-coil should lie along the membrane to prevent steric hindrances, resulting in only one ARF6 molecule bound. Such a heterotrimeric complex gives insights to better understand the ARF6-mediated motor switch regulatory function.
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PMID:The structural basis of Arf effector specificity: the crystal structure of ARF6 in a complex with JIP4. 1964 50

Invasion of cancer cells into collagen-rich extracellular matrix requires membrane-tethered membrane type 1-matrix metalloproteinase (MT1-MMP) as the key protease for collagen breakdown. Understanding how MT1-MMP is delivered to the surface of tumor cells is essential for cancer cell biology. In this study, we identify ARF6 together with c-Jun NH2-terminal kinase-interacting protein 3 and 4 (JIP3 and JIP4) effectors as critical regulators of this process. Silencing ARF6 or JIP3/JIP4 in breast tumor cells results in MT1-MMP endosome mispositioning and reduces MT1-MMP exocytosis and tumor cell invasion. JIPs are recruited by Wiskott-Aldrich syndrome protein and scar homologue (WASH) on MT1-MMP endosomes on which they recruit dynein-dynactin and kinesin-1. The interaction of plasma membrane ARF6 with endosomal JIPs coordinates dynactin-dynein and kinesin-1 activity in a tug-of-war mechanism, leading to MT1-MMP endosome tubulation and exocytosis. In addition, we find that ARF6, MT1-MMP, and kinesin-1 are up-regulated in high-grade triple-negative breast cancers. These data identify a critical ARF6-JIP-MT1-MMP-dynein-dynactin-kinesin-1 axis promoting an invasive phenotype of breast cancer cells.
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PMID:ARF6-JIP3/4 regulate endosomal tubules for MT1-MMP exocytosis in cancer invasion. 2650 63