Disease relevance of KIF5B

• A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10) [1].
• Attempts to identify a canonical kinesin heavy-chain gene or protein were unsuccessful, suggesting that a kinesin heavy chain may be absent or unnecessary for kinesin light-chain function in this eubacterium [2].
• We identified fasciculation and elongation protein zeta1 (FEZ1) as a binding partner of kinesin heavy chain [3].
• METHODS: Intrathoracally induced by HSV-TK30 transduced non-small cell lung cancer cell lines Colo 699 (adenocarcinoma) and KNS 62 (squamous cell carcinoma) were monitored for local tumor growth, survival, and metastases [4].
• Northern blots of total ribonucleic acid isolated from normal brain and a glioblastoma were probed with our KHC probe and confirmed the differential expression of this gene [5].

High impact information on KIF5B

• This mitochondrial phenotype was reversed by an exogenous expression of KIF5B, and a subcellular fractionation revealed that KIF5B is associated with mitochondria [6].
• Recent research has indicated that the principal component of kinesin, the kinesin heavy chain, is but one member of an extended superfamily of kinesin-like microtubule motor proteins [7].
• Although a single kinesin motor has been thought to serve all cell types, we document here that neurons express a second conventional kinesin heavy chain (nKHC) that is 65% identical in amino acid sequence to the ubiquitously expressed kinesin heavy chain (uKHC) [8].
• Inactive Kinesin-1 molecules are folded and autoinhibited such that the KHC tail blocks the initial interaction of the KHC motor with the microtubule [9].
• The recruitment of KHC to mitochondria is, in part, determined by the NH(2) terminus-splicing variant of milton [10].

Chemical compound and disease context of KIF5B

• We investigated the selective uptake of liposomes chemically modified by polysaccharides-cholesterol derivatives with 1-aminolactose (lactose) in two human hepatoma cell lines (HUH7 and Alexander), a human colon cancer cell line (FCC) and a human lung cancer cell line (KNS) [11].

Biological context of KIF5B

• Purification of the core-NF1 complex followed by mass spectrometric analysis revealed the motor protein, kinesin-1 heavy chain (HsuKHC/KIF5B), as a catalytic subunit of both NF-1-containing complexes [12].
• A human brain cDNA library was screened with a bait corresponding to amino acid residues 814-963 of human KIF5B [13].
• The major binding site for kinesin light chain in kinesin heavy chain was mapped to residues 789-813 at the C-terminal end of the heavy chain stalk domain [14].
• Imatinib, a known inhibitor of PDGFRalpha, produced a complete cytogenetic response and disappearance of the KIF5B-PDGFRA fusion by PCR, from both genomic DNA and mRNA [15].
• Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia [15].

Anatomical context of KIF5B

• Among them are several proteins in the membrane traffic pathway, such as the heavy and light chains (KHC/KIF5B and KLC2) of conventional kinesin, a heterotetrameric mechanochemical motor involved in the ATP-dependent movement of vesicles and organelles along microtubules [16].
• These foci (nucleoids) are tethered directly or indirectly through mitochondrial membranes to kinesin, marked by KIF5B, and microtubules in the surrounding cytoplasm [17].
• To understand the interactions between the microtubule-based motor protein kinesin and intracellular components, we have expressed the kinesin heavy chain and its different domains in CV-1 monkey kidney epithelial cells and examined their distributions by immunofluorescence microscopy [18].
• Kinesin heavy chain (HC) was expressed in COS cells either alone or with kinesin light chain (LC) [19].
• After transient expression in CV-1 cells, the kinesin heavy chain showed both a diffuse distribution and a filamentous staining pattern that coaligned with microtubules but not vimentin intermediate filaments [18].

Associations of KIF5B with chemical compounds

• The mutation occurs in the family in which the SPG10 locus was originally identified, at an invariant asparagine residue that, when mutated in orthologous kinesin heavy chain motor proteins, prevents stimulation of the motor ATPase by microtubule-binding [1].
• TNF treatment induced dissociation of the heavy chain kinesin family-5B (KIF5B) protein from tubulin in axons but not cell bodies as determined by lifetime-based F??rster resonance energy transfer (FRET) analysis [20].
• Altering the number and distribution of microtubules with taxol or nocodazole produced corresponding changes in the localization of the expressed kinesin heavy chain [18].
• The results point to a model in which one critical cysteine per kinesin heavy chain is relatively inaccessible to solvent [21].
• Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent [10].

Physical interactions of KIF5B

• The sites of interaction, determined from in vivo and in vitro assays, are the N-terminus of SNAP25 (residues 1-84) and the cargo-binding domain of kinesin heavy chain (residues 814-907) [14].
• Co-immunoprecipitation and confocal imaging strategies further showed that GRIF-1 can bind to the tetrameric kinesin light-chain/kinesin heavy-chain complex [22].
• DISC1 directly interacted with kinesin heavy chain of Kinesin-1 [23].
• Furthermore, p120 forms a complex with kinesin heavy chain through the p120 NH2-terminal head domain [24].

Regulatory relationships of KIF5B

• KIF5C and KIF5B are specifically expressed in a subset of neuroretinal cells and differentially localize with RanBP2 and importin-beta in distinct compartments [25].

Other interactions of KIF5B

• This screen identified the ribosome receptor, p180, as a KIF5B-binding protein [13].
• DISC1 formed a ternary complex with Grb2 and kinesin heavy chain KIF5A of Kinesin-1 [26].
• The human kinesin heavy chain exhibits a high level of sequence identity to the previously cloned invertebrate kinesin heavy chains; homologies between the COOH-terminal domain of human and invertebrate kinesins and the nonmotor domain of the Aspergillus kinesin-like protein bimC were also found [18].
• Colocalization studies further showed that the FMRP-GFP labeled granules also contained RNA, ribosomal subunits, kinesin heavy chain, and FXR1P molecules [27].
• Dual labeling with the squid myosin V antibody and a kinesin heavy chain antibody showed that the two motors colocalized on the same vesicles [28].

Analytical, diagnostic and therapeutic context of KIF5B

• In this study we employed a yeast two-hybrid assay to identify additional binding partners of the kinesin heavy chain isoform KIF5B [13].
• Amplification of the genomic breakpoint by bubble PCR revealed a novel fusion between KIF5B at 10p11 and PDGFRA at 4q12 [15].
• This predicted hydrophobic, alpha-helical coiled-coil interaction is supported by both circular dichroism spectroscopy of the recombinant kinesin heavy chain fragment 771-963, which displays an alpha-helical content of 70%, and the resistance of the heavy/light chain interaction to high salt (0.5 M) [29].
• Here, we report that the microinjection of KHC-specific antibodies into these cells has no effect on mitosis or ER membrane organization, even though one such antibody, SUK4, blocks kinesin-driven motility in vitro and in mammalian cells [30].
• Immunolocalization of kinesin at both the light and electron microscopy levels in NRK cells using the H1 monoclonal antibody to kinesin heavy chain, revealed kinesin to be associated with all membranes of the ER/Golgi system [31].

References