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)

Membrane transport of WAVE2 that leads to lamellipodia formation requires a small GTPase Rac1, the motor protein kinesin, and microtubules. Here we explore the possibility of whether the Rac1-dependent and kinesin-mediated WAVE2 transport along microtubules is regulated by a p21-activated kinase Pak as a downstream effector of Rac1. We find that Pak1 constitutively binds to WAVE2 and is transported with WAVE2 to the leading edge by stimulation with hepatocyte growth factor (HGF). Concomitantly, phosphorylation of tubulin-bound stathmin/Op18 at serine 25 (Ser25) and Ser38, microtubule growth, and stathmin/Op18 binding to kinesin-WAVE2 complex were induced. The HGF-induced WAVE2 transport, lamellipodia formation, stathmin/Op18 phosphorylation at Ser38 and binding to kinesin-WAVE2 complex, but not stathmin/Op18 phosphorylation at Ser25 and microtubule growth, were abrogated by Pak1 inhibitor IPA-3 and Pak1 depletion with small interfering RNA (siRNA). Moreover, stathmin/Op18 depletion with siRNA caused significant inhibition of HGF-induced WAVE2 transport and lamellipodia formation, with HGF-independent promotion of microtubule growth. Collectively, it is suggested that Pak1 plays a critical role in HGF-induced WAVE2 transport and lamellipodia formation by directing Pak1-WAVE2-kinesin complex toward the ends of growing microtubules through phosphorylation and recruitment of tubulin-bound stathmin/Op18 to the complex.
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PMID:Membrane transport of WAVE2 and lamellipodia formation require Pak1 that mediates phosphorylation and recruitment of stathmin/Op18 to Pak1-WAVE2-kinesin complex. 1916 78

Membrane targeting of WAVE2 along microtubules is mediated by a motor protein kinesin and requires Pak1, a downstream effector of Rac1. However, the mechanism by which WAVE2 targeting to the leading edge is directionally controlled remains largely unknown. Here we demonstrate that EB1, a microtubule plus-end-binding protein, constitutively associates with stathmin, a microtubule-destabilizing protein, in human breast cancer cells. Stimulation of the cells with insulin-like growth factor I (IGF-I) induced Pak1-dependent binding of the EB1-stathmin complex to microtubules that bear WAVE2 and colocalization of the complex with WAVE2 at the leading edge. Depletion of EB1 by small interfering RNA (siRNA) abrogated the IGF-I-induced WAVE2 targeting and stathmin binding to microtubules. On the other hand, chemotaxis chamber assays indicated that the IGF-I receptor (IGF-IR) was locally activated in the region facing toward IGF-I. In addition, IGF-I caused phosphatidylinositol 3-kinase (PI 3-kinase)-dependent production of phosphatidylinositol 3,4,5-triphosphate (PIP3) near activated IGF-IR and WAVE2 colocalization with it. Collectively, WAVE2-membrane targeting is directionally controlled by binding of the EB1-stathmin complex to WAVE2-bearing microtubules and by the interaction between WAVE2 and PIP3 produced near IGF-IR that is locally activated by IGF-I.
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PMID:Directional control of WAVE2 membrane targeting by EB1 and phosphatidylinositol 3,4,5-triphosphate. 1992 64

The neural cell adhesion molecule (NCAM, also known as NCAM1) is important during neural development, because it contributes to neurite outgrowth in response to its ligands at the cell surface. In the adult brain, NCAM is involved in regulating synaptic plasticity. The molecular mechanisms underlying delivery of NCAM to the neuronal cell surface remain poorly understood. We used a protein macroarray and identified the kinesin light chain 1 (KLC1), a component of the kinesin-1 motor protein, as a binding partner of the intracellular domains of the two transmembrane isoforms of NCAM, NCAM140 and NCAM180. KLC1 binds to amino acids CGKAGPGA within the intracellular domain of NCAM and colocalizes with kinesin-1 in the Golgi compartment. Delivery of NCAM180 to the cell surface is increased in CHO cells and neurons co-transfected with kinesin-1. We further demonstrate that the p21-activated kinase 1 (PAK1) competes with KLC1 for binding to the intracellular domain of NCAM and contributes to the regulation of the membrane insertion of NCAM. Our results indicate that NCAM is delivered to the cell surface through a kinesin-1-mediated transport mechanism in a PAK1-dependent manner.
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PMID:Kinesin-1 promotes post-Golgi trafficking of NCAM140 and NCAM180 to the cell surface. 2610 51