KBP interacts with SCG10, linking Goldberg-Shprintzen syndrome to microtubule dynamics and neuronal differentiation.
Goldberg-Shprintzen syndrome (GOSHS) is a rare clinical disorder characterized by central and enteric nervous system defects. This syndrome is caused by inactivating mutations in the Kinesin Binding Protein (KBP) gene, which encodes a protein of which the precise function is largely unclear. We show that KBP expression is up-regulated during neuronal development in mouse cortical neurons. Moreover, KBP-depleted PC12 cells were defective in nerve growth factor-induced differentiation and neurite outgrowth, suggesting that KBP is required for cell differentiation and neurite development. To identify KBP interacting proteins, we performed a yeast two-hybrid screen and found that KBP binds almost exclusively to microtubule associated or related proteins, specifically SCG10 and several kinesins. We confirmed these results by validating KBP interaction with one of these proteins: SCG10, a microtubule destabilizing protein. Zebrafish studies further demonstrated an epistatic interaction between KBP and SCG10 in vivo. To investigate the possibility of direct interaction between KBP and microtubules, we undertook co-localization and in vitro binding assays, but found no evidence of direct binding. Thus, our data indicate that KBP is involved in neuronal differentiation and that the central and enteric nervous system defects seen in GOSHS are likely caused by microtubule-related defects.
Alves
Maria M
MM
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Burzynski
Grzegorz
G
Delalande
Jean-Marie
JM
Osinga
Jan
J
van der Goot
Annemieke
A
Dolga
Amalia M
AM
de Graaff
Esther
E
Brooks
Alice S
AS
Metzger
Marco
M
Eisel
Ulrich L M
UL
Shepherd
Iain
I
Eggen
Bart J L
BJ
Hofstra
Robert M W
RM
D000818:Animals; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006367:HeLa Cells; D006627:Hirschsprung Disease / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008868:Microtubule Proteins; D008870:Microtubules / Q000378:metabolism*; D041681:NIH 3T3 Cells; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016716:PC12 Cells; D011485:Protein Binding; D051381:Rats; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D050777:Stathmin / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C554342:KBP protein, mouse; D008565:Membrane Proteins; D008868:Microtubule Proteins; C541121:SCG10 protein, zebrafish; D015843:Serpins; D050777:Stathmin; C512849:Stmn2 protein, mouse; C512848:Stmn2 protein, rat; D029961:Zebrafish Proteins; C051324:kallistatin; C527765:kif1bp protein, zebrafish