Interaction of Mint2 with TrkA is involved in regulation of nerve growth factor-induced neurite outgrowth.
TrkA receptor signaling is essential for nerve growth factor (NGF)-induced survival and differentiation of sensory neurons. To identify possible effectors or regulators of TrkA signaling, yeast two-hybrid screening was performed using the intracellular domain of TrkA as bait. We identified muc18-1-interacting protein 2 (Mint2) as a novel TrkA-binding protein and found that the phosphotyrosine binding domain of Mint2 interacted with TrkA in a phosphorylation- and ligand-independent fashion. Coimmunoprecipitation assays showed that endogenous TrkA interacted with Mint2 in rat tissue homogenates, and immunohistochemical evidence revealed that Mint2 and TrkA colocalized in rat dorsal root ganglion neurons. Furthermore, Mint2 overexpression inhibited NGF-induced neurite outgrowth in both PC12 and cultured dorsal root ganglion neurons, whereas inhibition of Mint2 expression by RNA interference facilitated NGF-induced neurite outgrowth. Moreover, Mint2 was found to promote the retention of TrkA in the Golgi apparatus and inhibit its surface sorting. Taken together, our data provide evidence that Mint2 is a novel TrkA-regulating protein that affects NGF-induced neurite outgrowth, possibly through a mechanism involving retention of TrkA in the Golgi apparatus.
Zhang
Yong
Y
Institute of Neuroscience and Key Laboratory of Molecular Neurobiology, Ministry of Education, Second Military Medical University, Shanghai 200433, China.
Wang
Yong-Gang
YG
Zhang
Qi
Q
Liu
Xiu-Jie
XJ
Liu
Xuan
X
Jiao
Li
L
Zhu
Wei
W
Zhang
Zhao-Huan
ZH
Zhao
Xiao-Lin
XL
He
Cheng
C
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation / Q000502:physiology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
C491636:APBA2 protein, human; C109650:Apba2 protein, rat; D015820:Cadherins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D020932:Nerve Growth Factor; D020917:Receptor, trkA