Function of JIP1 in Promoting Axonal Growth

2018-09-21

Introduction 

JIP1, a member of the JIPs family, was first discovered to promote JNK activation by combining multiple components of the JNK signaling pathway. JIP1 also has a JNK-binding domain (JBD) at the N-terminus, a SH3 region at the C-terminus, and a phosphotyrosine-binding domain (PTB) also located at the C-terminus. Studies have found that in the nervous system, JIP1 can also act as a scaffold protein to mediate the transport of a variety of goods.

Pharmacologic action

Overexpression of JIP1 can increase the number and length of filopodia at the axon end. Because the filopodia are prominent in the actin-rich plasma membrane, the promotion of JIP1 to axon growth may be related to the filiform pseudo-based based on F-actin dynamics. The dominant negative phase mutant of JNK3 for JNK can further significantly reduce the activity of cofilin and the polymerization of actin by reducing the level of acidification of JNK at the end of axon. Simultaneously, overexpression of JIP1 enhances the activity of cofilin at the axon end. The activated cofilin enhances the assembly of actin fibers. Overexpression of JIP1 can significantly increase the content of F-actin. When overexpressing cofilin S3E, a persistent inactivating mutant of cofilin, JIP1 lost its contribution to axonal growth, suggesting that cofilin activity is critical for JIP1 to promote axon growth.

Function

JIP1 specifically activates JNK at the end of a neuronal axon, but has no significant effect on JNK at the cell site of the neuron. JIP1 can ultimately promote axonal growth by being transported to the axon end and at the end by enhancing the activity of JNK and cofilin and regulating F-actin dynamics. JIP has no effect on the axon specialization, and for axonal growth it can be transported to the end of the axon and promote JNK phosphorylation at the end to produce a potentiation.

Pharmacokinetics and metabolism

The JIP1 plasma protein binding rate is 0.5 and is excreted by the kidney. JIP1 is excreted in the urine at a 25% rate after administration of 17 μg/kg i.m. JIP1 is metabolized and converted to inactive substances. JIP1 has an induction or inhibition effect on liver drug enzymes, which is directly related to the rate of drug clearance and changes the duration and intensity of drug action.

References:

1. Burack, M. A., Silverman, M. A., & Banker, G. (2000). The role of selective transport in neuronal protein sorting. Neuron, 26(2), 465-472.

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