Mapping the GRIF-1 Binding Domain of the Kinesin, KIF5C, Substantiates a Role for GRIF-1 as an Adaptor Protein in the Anterograde Trafficking of Cargoes

Smith, Miriam J.; Pozo, Karine; Brickley, Kieran; Stephenson, F. Anne

doi:10.1074/jbc.m600522200

Cited by 76 publications

(80 citation statements)

References 30 publications

(47 reference statements)

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“…These are genetically distinct proteins with little homology (Saito et al, 1997). Specific regions of a number of kinesins that interact with and bind to cargo have been identified previously (Hirokawa, 1998;Verhey et al, 2001;Smith et al, 2006). In particular, previous studies of Kifc1 identified a 19-amino acid sequence that is required for binding to membrane-bounded organelles (Zhang and Sperry, 2004).…”

Section: Discussionmentioning

confidence: 99%

Kif5B and Kifc1 Interact and Are Required for Motility and Fission of Early Endocytic Vesicles in Mouse Liver

Nath

Bananis

Sarkar

et al. 2007

MBoC

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Early endocytic vesicles loaded with Texas Red asialoorosomucoid were prepared from mouse liver. These vesicles bound to microtubules in vitro, and upon ATP addition, they moved bidirectionally, frequently undergoing fission into two daughter vesicles. There was no effect of vanadate (inhibitor of dynein) on motility, whereas 5 -adenylylimido-diphosphate (kinesin inhibitor) was highly inhibitory. Studies with specific antibodies confirmed that dynein was not associated with these vesicles and that Kif5B and the minus-end kinesin Kifc1 mediated their plus-and minus-end motility, respectively. More than 90% of vesicles associated with Kifc1 also contained Kif5B, and inhibition of Kifc1 with antibody resulted in enhancement of plus-end-directed motility. There was reduced vesicle fission when either Kifc1 or Kif5B activity was inhibited by antibody, indicating that the opposing forces resulting from activity of both motors are required for fission to occur. Immunoprecipitation of native Kif5B by FLAG antibody after expression of FLAG-Kifc1 in 293T cells indicates that these two motors can interact with each other. Whether they interact directly or through a complex of potential regulatory proteins will need to be clarified in future studies. However, the present study shows that coordinated activity of these kinesins is essential for motility and processing of early endocytic vesicles. INTRODUCTIONReceptor-mediated endocytosis is a process in which ligands bind to specific cell surface receptors and internalize via clathrin-coated pits. After internalization the clathrin coat is released and uncoated vesicles mature into early endosomes (Mellman, 1996;Mukherjee et al., 1997;Marsh and McMahon, 1999;Higgins and McMahon, 2002;Perrais and Merrifield, 2005). After acidification of early endosomes, ligands such as asialoorosomucoid (ASOR) that are destined for lysosomes dissociate from their receptors (Harford et al., 1983a,b), and a series of fission events results in their segregation into separate daughter vesicles (Wolkoff et al., 1984;Mellman, 1996;Mukherjee et al., 1997;Murray and Wolkoff, 2003). The resulting ligand-enriched late endosomes traffic to lysosomes for degradation, whereas the receptor-containing daughter endosomes traffic back to the cell surface where receptor is reused (Harford et al., 1983a;Wolkoff et al., 1984;Mukherjee et al., 1997). Previous studies indicated that this segregation event requires an intact microtubule cytoskeleton (Goltz et al., 1992;Novikoff et al., 1996;Murray et al., 2000;Bananis et al., 2003Bananis et al., , 2004. In more recent studies, microtubule-based endosome motility and segregation were reconstituted in vitro using fluorescent early endosomes prepared from rat liver 5 min after portal venous injection of Texas Red-labeled ASOR, a substrate for the hepatocytespecific asialoglycoprotein receptor (ASGPR) (Bananis et al., , 2003(Bananis et al., , 2004Murray et al., 2000;Murray and Wolkoff, 2003). On addition of ATP to the in vitro assay, these vesicles moved bidirectionall...

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Section: Discussionmentioning

confidence: 99%

Kif5B and Kifc1 Interact and Are Required for Motility and Fission of Early Endocytic Vesicles in Mouse Liver

Nath

Bananis

Sarkar

et al. 2007

MBoC

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“…12; pDsRed1-Mito for visualization of mitochondria, pECFP-TRAK2, and pKIF5C-EYFP were as in Ref. 13; and pECFP-hTRAK1 was as in Ref. 16.…”

Section: Methodsmentioning

confidence: 99%

“…9, and in-house rabbit anti-FLAG antibodies were generated as in Ref. 13. Anti-His G and antirabbit Alexa Fluor 680 antibodies were from Invitrogen; anti-GFP antibodies were from Abcam Ltd. (Cambridge, UK); anti-␤-actin antibodies were from Sigma-Aldrich; and rabbit, mouse, and sheep horseradish peroxidase-linked secondary antibodies were from Amersham Biosciences.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, TRAK1, TRAK2, or Milton each co-immunoprecipitate with KHC from detergent extracts of neuronal tissue (11,12). The association between the TRAKs and KHC is direct and involves interaction between TRAKs and the KHC non-motor, C-terminal cargo binding domain (13). In heterologous expression, TRAKs and Milton are targeted to mitochondria (11,12,14).…”

mentioning

confidence: 99%

“…In heterologous expression, TRAKs and Milton are targeted to mitochondria (11,12,14). The co-expression of TRAK1, TRAK2, or Milton with KHC results in the redistribution of mitochondria such that they colocalize with TRAK1, TRAK2, Milton, and kinesin heavy chains at the tips of cellular processes (13,15,16). Miro1 and Miro2 co-distribute and co-immunoprecipitate with Milton, TRAK1, or TRAK2 following overexpression in mammalian cells (15,16,17).…”

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Trafficking Kinesin Protein (TRAK)-mediated Transport of Mitochondria in Axons of Hippocampal Neurons

Brickley

Stephenson

2011

Journal of Biological Chemistry

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156

127

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In neurons, the proper distribution of mitochondria is essential because of a requirement for high energy and calcium buffering during synaptic neurotransmission. The efficient, regulated transport of mitochondria along axons to synapses is therefore crucial for maintaining function. The trafficking kinesin protein (TRAK)/Milton family of proteins comprises kinesin adaptors that have been implicated in the neuronal trafficking of mitochondria via their association with the mitochondrial protein Miro and kinesin motors. In this study, we used gene silencing by targeted shRNAi and dominant negative approaches in conjunction with live imaging to investigate the contribution of endogenous TRAKs, TRAK1 and TRAK2, to the transport of mitochondria in axons of hippocampal pyramidal neurons. We report that both strategies resulted in impairing mitochondrial mobility in axonal processes. Differences were apparent in terms of the contribution of TRAK1 and TRAK2 to this transport because knockdown of TRAK1 but not TRAK2 impaired mitochondrial mobility, yet both TRAK1 and TRAK2 were shown to rescue transport impaired by TRAK1 gene knock-out. Thus, we demonstrate for the first time the pivotal contribution of the endogenous TRAK family of kinesin adaptors to the regulation of mitochondrial mobility.Mitochondria serve several functions in cells. These functions include the generation of energy in the form of ATP, the buffering of calcium ions, and the regulation of apoptosis. Thus, within cells, mitochondria need to move so they can respond to local needs. In the nervous system, mitochondria and mitochondrial transport are particularly important because of a requirement for high energy and calcium buffering during synaptic neurotransmission. The mitochondrial population in neurons is therefore highly mobile, and the dynamics of their transport are tightly regulated to satisfy these demands. Mitochondria can move in both anterograde and retrograde directions, utilizing motor proteins and the microtubule network (for reviews, see Refs. 1-3). Furthermore, they can be anchored at defined sites; one example is mitochondrial immobilization by a Ca 2ϩ -dependent mechanism at synaptic sites (4 -7). Recently, there has been significant progress in the understanding of mitochondrial transport processes with the identification of several proteins implicated in their trafficking mechanisms.The best characterized of these include the trafficking kinesin protein (TRAK) 2 /Milton family of kinesin adaptors; Miro1 and Miro2, atypical Rho GTPases that reside in the mitochondrial outer membrane that are purported receptors for TRAKs; syntabulin, also a kinesin adaptor protein; and syntaphilin, an axonal mitochondrial docking protein (for reviews, see Refs. 3 and 8).There are two mammalian TRAKs, TRAK1 and TRAK2, that share ϳ58% amino acid homology (9, 10). The TRAKs, like their Drosophila orthologue Milton (11), have been shown to function as kinesin adaptors linking kinesin heavy chain (KHC) to mitochondria by their association with Miro1/2. T...

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Neuronal Mitochondrial Transport

Knight

Chen

Sun

et al. 2015

The Functions, Disease‐Related Dysfunctions, and Therapeutic Targeting of Neuronal Mitochondria

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Mapping the GRIF-1 Binding Domain of the Kinesin, KIF5C, Substantiates a Role for GRIF-1 as an Adaptor Protein in the Anterograde Trafficking of Cargoes

Cited by 76 publications

References 30 publications

Kif5B and Kifc1 Interact and Are Required for Motility and Fission of Early Endocytic Vesicles in Mouse Liver

Kif5B and Kifc1 Interact and Are Required for Motility and Fission of Early Endocytic Vesicles in Mouse Liver

Trafficking Kinesin Protein (TRAK)-mediated Transport of Mitochondria in Axons of Hippocampal Neurons

Neuronal Mitochondrial Transport

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