Kinesin-2家族在模式生物中的功能研究进展
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摘要
Kinesin-2蛋白是Kinesin超级蛋白家族的一个亚家族,成员包括KIF3A,KIF3B,KIF3C以及KIF17。作为分子马达蛋白,Kinesin-2家族成员参与了细胞内多种蛋白复合体及囊泡的运输,对细胞行使各种生物学功能非常重要。近年来发现Kinesin-2在纤毛内物质运输方面发挥重要作用,其功能缺陷可导致纤毛发育异常,进而影响组织器官的发育,并最终导致多种纤毛疾病的形成。本综述将对近期Kinesin-2的研究进展进行介绍,将着重介绍kinesin-2家族成员在模式生物研究中的新进展。
Kinesin-2 family proteins,including KIF3 A,KIF3B,KIF3 C and KIF17,are members of the kinesin superfamily motor proteins,which transport various proteins and vesicles in the cell and play diverse biological functions.Recently,studies on members of kinesin-2 family proteins suggest that they play fundamental roles during ciliary transport,whose defects can lead to abnormal cilia development,the major cause of human ciliopathies. In this review,we will summarize the functions of this motor protein family during ciliogenesis and focus mainly on their roles in the development of model organisms.
Kinesin-2 family proteins,including KIF3 A,KIF3B,KIF3 C and KIF17,are members of the kinesin superfamily motor proteins,which transport various proteins and vesicles in the cell and play diverse biological functions.Recently,studies on members of kinesin-2 family proteins suggest that they play fundamental roles during ciliary transport,whose defects can lead to abnormal cilia development,the major cause of human ciliopathies. In this review,we will summarize the functions of this motor protein family during ciliogenesis and focus mainly on their roles in the development of model organisms.
引文
[1]Hirokawa N,Tanaka Y.Kinesin superfamily proteins(KIFs):Various functions and their relevance for important phenomena in life and diseases[J].Exp Cell Res,2015,334(1):16-25.
[2]Satir P,Christensen ST.Overview of structure and function of mammalian cilia[J].Annual Rev Physiol,2007,69:377-400.
[3]Goetz SC,Anderson KV.The primary cilium:a signalling centre during vertebrate development[J].Nature Rev Genet,2010,11(5):331-344.
[4]Oh EC,Katsanis N.Cilia in vertebrate development and disease[J].Development,2012,139(3):443-448.
[5]Hildebrandt F,Benzing T,Katsanis N.Ciliopathies[J].New Engl J Med,2011,364(16):1533-1543.
[6]Scholey JM.Kinesin-2:a family of heterotrimeric and homodimeric motors with diverse intracellular transport functions[J].Annu Rev Cell Dev Biol,2013,29:443-469.
[7]Huang CJ,Huang CC,Chang CC.Association of the testis-specific TRIM/RBCC protein RNF33/TRIM60 with the cytoplasmic motor proteins KIF3A and KIF3B[J].Mol Cellular Biochem,2012,360(1-2):121-131.
[8]Muresan V,Abramson T,Lyass A et al.KIF3C and KIF3A form a novel neuronal heteromeric kinesin that associates with membrane vesicles[J].Mol Biol Cell,1998,9(3):637-652.
[9]Kozminski KG,Johnson KA,Forscher P et al.A motility in the eukaryotic flagellum unrelated to flagellar beating[J].Proc Nat Acad Sci U S A,1993,90(12):5519-5523.
[10]Cole DG,Snell WJ.Snap shot:Intraflagellar transport[J].Cell,2009,137(4):784-784 e781.
[11]Taschner M,Bhogaraju S,Lorentzen E.Architecture and function of IFT complex proteins in ciliogenesis[J].Different Res Biol Diversity,2012,83(2):S12-22.
[12]Kozminski KG,Beech PL,Rosenbaum JL.The Chlamydomonas kinesin-like protein FLA10 is involved in motility associated with the flagellar membrane[J].J Cell Biol,1995,131(6 Pt 1):1517-1527.
[13]Walther Z,Vashishtha M,Hall JL.The Chlamydomonas FLA10gene encodes a novel kinesin-homologous protein[J].J Cell Biol,1994,126(1):175-188.
[14]Pan J,Snell WJ.Kinesin-II is required for flagellar sensory transduction during fertilization in Chlamydomonas[J].Mol Biol Cell,2002,13(4):1417-1426.
[15]Liang Y,Pang Y,Wu Q et al.FLA8/KIF3B phosphorylation regulates kinesin-II interaction with IFT-B to control IFT entry and turnaround[J].Dev Cell,2014,30(5):585-597.
[16]Perkins LA,Hedgecock EM,Thomson JN et al.Mutant sensory cilia in the nematode Caenorhabditis elegans[J].Dev Biol,1986,117(2):456-487.
[17]Pan X,Ou G,Civelekoglu-Scholey G et al.Mechanism of transport of IFT particles in C.elegans cilia by the concerted action of kinesin-II and OSM-3 motors[J].J Cell Biol,2006,174(7):1035-1045.
[18]Snow JJ,Ou G,Gunnarson AL et al.Two anterograde intraflagellar transport motors cooperate to build sensory cilia on C.elegans neurons[J].Nature Cell Biol,2004,6(11):1109-1113.
[19]Ou G,Blacque OE,Snow JJ et al.Functional coordination of intraflagellar transport motors[J].Nature,2005,436(7050):583-587.
[20]Mukhopadhyay S,Lu Y,Qin H et al.Distinct IFT mechanisms contribute to the generation of ciliary structural diversity in C.elegans[J].EMBO J,2007,26(12):2966-2980.
[21]Morsci NS,Barr MM.Kinesin-3 KLP-6 regulates intraflagellar transport in male-specific cilia of Caenorhabditis elegans[J].Curr Biol:CB,2011,21(14):1239-1244.
[22]Hao L,Thein M,Brust-Mascher I et al.Intraflagellar transport delivers tubulin isotypes to sensory cilium middle and distal segments[J].Nature Cell Biol,2011,13(7):790-798.
[23]Zhao C,Omori Y,Brodowska K et al.Kinesin-2 family in vertebrate ciliogenesis[J].Proc Nat Acad Sci U S A,2012,109(7):2388-2393.
[24]Insinna C,Humby M,Sedmak T et al.Different roles for KIF17and kinesin II in photoreceptor development and maintenance[J].Dev Dyn,2009,238(9):2211-2222.
[25]Ryan S,Willer J,Marjoram L et al.Rapid identification of kidney cyst mutations by whole exome sequencing in zebrafish[J].Development,2013,140(21):4445-4451.
[26]Insinna C,Pathak N,Perkins B et al.The homodimeric kinesin,Kif17,is essential for vertebrate photoreceptor sensory outer segment development[J].Dev Biol,2008,316(1):160-170.
[27]Kok FO,Shin M,Ni CW et al.Reverse genetic screening reveals poor correlation between morpholino-induced and mutant phenotypes in zebrafish[J].Dev Cell,2015,32(1):97-108.
[28]Rossi A,Kontarakis Z,Gerri C et al.Genetic compensation induced by deleterious mutations but not gene knockdowns[J].Nature,2015,524:230-233.
[29]Kondo S,Sato-Yoshitake R,Noda Y et al.KIF3A is a new microtubule-based anterograde motor in the nerve axon[J].J Cell Biol,1994,125(5):1095-1107.
[30]Marszalek JR,Ruiz-Lozano P,Roberts E et al.Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II[J].Proc Nat Acad Sci U S A,1999,96(9):5043-5048.
[31]Marszalek JR,Liu X,Roberts EA et al.Genetic evidence for selective transport of opsin and arrestin by kinesin-II in mammalian photoreceptors[J].Cell,2000,102(2):175-187.
[32]Koyama E,Young B,Nagayama M et al.Conditional Kif3a ablation causes abnormal hedgehog signaling topography,growth plate dysfunction,and excessive bone and cartilage formation during mouse skeletogenesis[J].Development,2007,134(11):2159-2169.
[33]Liu B,Chen S,Johnson C et al.A ciliopathy with hydrocephalus,isolated craniosynostosis,hypertelorism,and clefting caused by deletion of Kif3a[J].Reprod Toxicol,2014,48:88-97.
[34]Lin F,Hiesberger T,Cordes K et al.Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease[J].Proc Nat Acad Sci U S A,2003,100(9):5286-5291.
[35]Qiu N,Xiao Z,Cao L et al.Disruption of Kif3a in osteoblasts results in defective bone formation and osteopenia[J].J Cell Sci,2012,125(Pt 8):1945-1957.
[36]Sipe CW,Lu X.Kif3a regulates planar polarization of auditory hair cells through both ciliary and non-ciliary mechanisms[J].Development,2011,138(16):3441-3449.
[37]Corbit KC,Shyer AE,Dowdle WE et al.Kif3a constrains betacatenin-dependent Wnt signalling through dual ciliary and nonciliary mechanisms[J].Nature Cell Biol,2008,10(1):70-76.
[38]Yamazaki H,Nakata T,Okada Y et al.KIF3A/B:a heterodimeric kinesin superfamily protein that works as a microtubule plus end-directed motor for membrane organelle transport[J].J Cell Biol,1995,130(6):1387-1399.
[39]Nonaka S,Tanaka Y,Okada Y et al.Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein[J].Cell,1998,95(6):829-837.
[40]Yang Z,Goldstein LS.Characterization of the KIF3C neural kinesin-like motor from mouse[J].Mol Biol Cell,1998,9(2):249-261.
[41]Yang Z,Roberts EA,Goldstein LS.Functional analysis of mouse kinesin motor Kif3C[J].Mol Cell Biol,2001,21(16):5306-5311.
[42]Gumy LF,Chew DJ,Tortosa E et al.The kinesin-2 family member KIF3C regulates microtubule dynamics and is required for axon growth and regeneration[J].J Neurosci,2013,33(28):11329-11345.
[43]Yin X,Takei Y,Kido MA et al.Molecular motor KIF17 is fundamental for memory and learning via differential support of synaptic NR2A/2B levels[J].Neuron,2011,70(2):310-325.
[44]Guillaud L,Setou M,Hirokawa N.KIF17 dynamics and regulation of NR2B trafficking in hippocampal neurons[J].J Neurosci,2003,23(1):131-140.
[45]Wong RW,Setou M,Teng J et al.Overexpression of motor protein KIF17 enhances spatial and working memory in transgenic mice[J].Proc Nat Acad Sci U S A,2002,99(22):14500-14505.
[46]Setou M,Nakagawa T,Seog DH et al.Kinesin superfamily motor protein KIF17 and m Lin-10 in NMDA receptor-containing vesicle transport[J].Science,2000,288(5472):1796-1802.
[47]Cole DG,Chinn SW,Wedaman KP et al.Novel heterotrimeric kinesin-related protein purified from sea urchin eggs[J].Nature,1993,366(6452):268-270.
[48]Sarpal R,Todi SV,Sivan-Loukianova E et al.Drosophila KAP interacts with the kinesin II motor subunit KLP64D to assemble chordotonal sensory cilia,but not sperm tails[J].Cur Biol,2003,13(19):1687-1696.
[49]Ray K,Perez SE,Yang Z et al.Kinesin-II is required for axonal transport of choline acetyltransferase in Drosophila[J].J Cell Biol,1999,147(3):507-518.
[50]Vuong LT,Mukhopadhyay B,Choi KW.Kinesin-II recruits Armadillo and Dishevelled for Wingless signaling in Drosophila[J].Development,2014,141(16):3222-3232.
[51]Niwa S,Nakajima K,Miki H et al.KIF19A is a microtubule-depolymerizing kinesin for ciliary length control[J].Dev Cell,2012,23(6):1167-1175.
[52]He M,Subramanian R,Bangs F et al.The kinesin-4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment[J].Nature Cell Biol,2014,16(7):663-672.
[53]Kobayashi T,Tsang WY,Li J et al.Centriolar kinesin Kif24 interacts with CP110 to remodel microtubules and regulate ciliogenesis[J].Cell,2011,145(6):914-925.
[2]Satir P,Christensen ST.Overview of structure and function of mammalian cilia[J].Annual Rev Physiol,2007,69:377-400.
[3]Goetz SC,Anderson KV.The primary cilium:a signalling centre during vertebrate development[J].Nature Rev Genet,2010,11(5):331-344.
[4]Oh EC,Katsanis N.Cilia in vertebrate development and disease[J].Development,2012,139(3):443-448.
[5]Hildebrandt F,Benzing T,Katsanis N.Ciliopathies[J].New Engl J Med,2011,364(16):1533-1543.
[6]Scholey JM.Kinesin-2:a family of heterotrimeric and homodimeric motors with diverse intracellular transport functions[J].Annu Rev Cell Dev Biol,2013,29:443-469.
[7]Huang CJ,Huang CC,Chang CC.Association of the testis-specific TRIM/RBCC protein RNF33/TRIM60 with the cytoplasmic motor proteins KIF3A and KIF3B[J].Mol Cellular Biochem,2012,360(1-2):121-131.
[8]Muresan V,Abramson T,Lyass A et al.KIF3C and KIF3A form a novel neuronal heteromeric kinesin that associates with membrane vesicles[J].Mol Biol Cell,1998,9(3):637-652.
[9]Kozminski KG,Johnson KA,Forscher P et al.A motility in the eukaryotic flagellum unrelated to flagellar beating[J].Proc Nat Acad Sci U S A,1993,90(12):5519-5523.
[10]Cole DG,Snell WJ.Snap shot:Intraflagellar transport[J].Cell,2009,137(4):784-784 e781.
[11]Taschner M,Bhogaraju S,Lorentzen E.Architecture and function of IFT complex proteins in ciliogenesis[J].Different Res Biol Diversity,2012,83(2):S12-22.
[12]Kozminski KG,Beech PL,Rosenbaum JL.The Chlamydomonas kinesin-like protein FLA10 is involved in motility associated with the flagellar membrane[J].J Cell Biol,1995,131(6 Pt 1):1517-1527.
[13]Walther Z,Vashishtha M,Hall JL.The Chlamydomonas FLA10gene encodes a novel kinesin-homologous protein[J].J Cell Biol,1994,126(1):175-188.
[14]Pan J,Snell WJ.Kinesin-II is required for flagellar sensory transduction during fertilization in Chlamydomonas[J].Mol Biol Cell,2002,13(4):1417-1426.
[15]Liang Y,Pang Y,Wu Q et al.FLA8/KIF3B phosphorylation regulates kinesin-II interaction with IFT-B to control IFT entry and turnaround[J].Dev Cell,2014,30(5):585-597.
[16]Perkins LA,Hedgecock EM,Thomson JN et al.Mutant sensory cilia in the nematode Caenorhabditis elegans[J].Dev Biol,1986,117(2):456-487.
[17]Pan X,Ou G,Civelekoglu-Scholey G et al.Mechanism of transport of IFT particles in C.elegans cilia by the concerted action of kinesin-II and OSM-3 motors[J].J Cell Biol,2006,174(7):1035-1045.
[18]Snow JJ,Ou G,Gunnarson AL et al.Two anterograde intraflagellar transport motors cooperate to build sensory cilia on C.elegans neurons[J].Nature Cell Biol,2004,6(11):1109-1113.
[19]Ou G,Blacque OE,Snow JJ et al.Functional coordination of intraflagellar transport motors[J].Nature,2005,436(7050):583-587.
[20]Mukhopadhyay S,Lu Y,Qin H et al.Distinct IFT mechanisms contribute to the generation of ciliary structural diversity in C.elegans[J].EMBO J,2007,26(12):2966-2980.
[21]Morsci NS,Barr MM.Kinesin-3 KLP-6 regulates intraflagellar transport in male-specific cilia of Caenorhabditis elegans[J].Curr Biol:CB,2011,21(14):1239-1244.
[22]Hao L,Thein M,Brust-Mascher I et al.Intraflagellar transport delivers tubulin isotypes to sensory cilium middle and distal segments[J].Nature Cell Biol,2011,13(7):790-798.
[23]Zhao C,Omori Y,Brodowska K et al.Kinesin-2 family in vertebrate ciliogenesis[J].Proc Nat Acad Sci U S A,2012,109(7):2388-2393.
[24]Insinna C,Humby M,Sedmak T et al.Different roles for KIF17and kinesin II in photoreceptor development and maintenance[J].Dev Dyn,2009,238(9):2211-2222.
[25]Ryan S,Willer J,Marjoram L et al.Rapid identification of kidney cyst mutations by whole exome sequencing in zebrafish[J].Development,2013,140(21):4445-4451.
[26]Insinna C,Pathak N,Perkins B et al.The homodimeric kinesin,Kif17,is essential for vertebrate photoreceptor sensory outer segment development[J].Dev Biol,2008,316(1):160-170.
[27]Kok FO,Shin M,Ni CW et al.Reverse genetic screening reveals poor correlation between morpholino-induced and mutant phenotypes in zebrafish[J].Dev Cell,2015,32(1):97-108.
[28]Rossi A,Kontarakis Z,Gerri C et al.Genetic compensation induced by deleterious mutations but not gene knockdowns[J].Nature,2015,524:230-233.
[29]Kondo S,Sato-Yoshitake R,Noda Y et al.KIF3A is a new microtubule-based anterograde motor in the nerve axon[J].J Cell Biol,1994,125(5):1095-1107.
[30]Marszalek JR,Ruiz-Lozano P,Roberts E et al.Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II[J].Proc Nat Acad Sci U S A,1999,96(9):5043-5048.
[31]Marszalek JR,Liu X,Roberts EA et al.Genetic evidence for selective transport of opsin and arrestin by kinesin-II in mammalian photoreceptors[J].Cell,2000,102(2):175-187.
[32]Koyama E,Young B,Nagayama M et al.Conditional Kif3a ablation causes abnormal hedgehog signaling topography,growth plate dysfunction,and excessive bone and cartilage formation during mouse skeletogenesis[J].Development,2007,134(11):2159-2169.
[33]Liu B,Chen S,Johnson C et al.A ciliopathy with hydrocephalus,isolated craniosynostosis,hypertelorism,and clefting caused by deletion of Kif3a[J].Reprod Toxicol,2014,48:88-97.
[34]Lin F,Hiesberger T,Cordes K et al.Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease[J].Proc Nat Acad Sci U S A,2003,100(9):5286-5291.
[35]Qiu N,Xiao Z,Cao L et al.Disruption of Kif3a in osteoblasts results in defective bone formation and osteopenia[J].J Cell Sci,2012,125(Pt 8):1945-1957.
[36]Sipe CW,Lu X.Kif3a regulates planar polarization of auditory hair cells through both ciliary and non-ciliary mechanisms[J].Development,2011,138(16):3441-3449.
[37]Corbit KC,Shyer AE,Dowdle WE et al.Kif3a constrains betacatenin-dependent Wnt signalling through dual ciliary and nonciliary mechanisms[J].Nature Cell Biol,2008,10(1):70-76.
[38]Yamazaki H,Nakata T,Okada Y et al.KIF3A/B:a heterodimeric kinesin superfamily protein that works as a microtubule plus end-directed motor for membrane organelle transport[J].J Cell Biol,1995,130(6):1387-1399.
[39]Nonaka S,Tanaka Y,Okada Y et al.Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein[J].Cell,1998,95(6):829-837.
[40]Yang Z,Goldstein LS.Characterization of the KIF3C neural kinesin-like motor from mouse[J].Mol Biol Cell,1998,9(2):249-261.
[41]Yang Z,Roberts EA,Goldstein LS.Functional analysis of mouse kinesin motor Kif3C[J].Mol Cell Biol,2001,21(16):5306-5311.
[42]Gumy LF,Chew DJ,Tortosa E et al.The kinesin-2 family member KIF3C regulates microtubule dynamics and is required for axon growth and regeneration[J].J Neurosci,2013,33(28):11329-11345.
[43]Yin X,Takei Y,Kido MA et al.Molecular motor KIF17 is fundamental for memory and learning via differential support of synaptic NR2A/2B levels[J].Neuron,2011,70(2):310-325.
[44]Guillaud L,Setou M,Hirokawa N.KIF17 dynamics and regulation of NR2B trafficking in hippocampal neurons[J].J Neurosci,2003,23(1):131-140.
[45]Wong RW,Setou M,Teng J et al.Overexpression of motor protein KIF17 enhances spatial and working memory in transgenic mice[J].Proc Nat Acad Sci U S A,2002,99(22):14500-14505.
[46]Setou M,Nakagawa T,Seog DH et al.Kinesin superfamily motor protein KIF17 and m Lin-10 in NMDA receptor-containing vesicle transport[J].Science,2000,288(5472):1796-1802.
[47]Cole DG,Chinn SW,Wedaman KP et al.Novel heterotrimeric kinesin-related protein purified from sea urchin eggs[J].Nature,1993,366(6452):268-270.
[48]Sarpal R,Todi SV,Sivan-Loukianova E et al.Drosophila KAP interacts with the kinesin II motor subunit KLP64D to assemble chordotonal sensory cilia,but not sperm tails[J].Cur Biol,2003,13(19):1687-1696.
[49]Ray K,Perez SE,Yang Z et al.Kinesin-II is required for axonal transport of choline acetyltransferase in Drosophila[J].J Cell Biol,1999,147(3):507-518.
[50]Vuong LT,Mukhopadhyay B,Choi KW.Kinesin-II recruits Armadillo and Dishevelled for Wingless signaling in Drosophila[J].Development,2014,141(16):3222-3232.
[51]Niwa S,Nakajima K,Miki H et al.KIF19A is a microtubule-depolymerizing kinesin for ciliary length control[J].Dev Cell,2012,23(6):1167-1175.
[52]He M,Subramanian R,Bangs F et al.The kinesin-4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment[J].Nature Cell Biol,2014,16(7):663-672.
[53]Kobayashi T,Tsang WY,Li J et al.Centriolar kinesin Kif24 interacts with CP110 to remodel microtubules and regulate ciliogenesis[J].Cell,2011,145(6):914-925.