PTPRM - Cell Migration - Neurite Outgrowth

Neurite Outgrowth

PTPmu is expressed in the developing brain and retina. A brain cell, or neuron, has a cell body that contains the nucleus and two types of extensions or processes that grow out from the cell body, the dendrites and axons. Dendrites generally receive input from other neurons, while axons send output to adjacent neurons. These processes are called neurites when grown ‘’in vitro’’ on tissue culture plates, because it is not clear whether they are dendrites or axons. ‘’In vitro’’ growth studies are useful for evaluating the mechanisms that neurons use to grow and function. A neurite outgrowth assay is a type of experiment where neurons are placed on different adhesive substrates on tissue culture plates. A neurite outgrowth assay is meant to mimic how neurons grow inside the body. During development of the nervous system, neuronal axons reach their often-distant targets by reacting to different substrates in their environment, so-called guidance cues, that are attractive, repulsive or simply permissive, meaning these substrates pull axons toward them, away from them, or act in a way that allows growth, respectively. When PTPmu is applied to a dish as an ‘’in vitro’’ substrate, it promotes neurite outgrowth. PTPmu also acts as a guidance cue during development of the nervous system, by repelling neurites of the temporal neural retina, while permitting growth of neurites from the nasal neural retina. Expression of PTPmu protein capable of dephosphorylating tyrosine residues is required for mediating both nasal neurite outgrowth and temporal neurite repulsion. By blocking the expression of PTPmu protein with antisense technology, or by expressing catalytically inactive mutants of PTPmu (molecules of PTPmu that can not dephosphorylate their target proteins) in the developing retina, it was shown that PTPmu is required for the development of the neural retina.

PTPmu also regulates neurite outgrowth on classical cadherins. PTPmu tyrosine phosphatase activity is necessary for neurite outgrowth on the classical cadherins E-, N- and R-cadherin, suggesting that PTPmu dephosphorylates key components of the cadherin-catenin complex to regulate axonal migration. Again, this emphasizes that PTPmu likely regulates cadherin-dependent processes via its cytoplasmic domain.

Various signals required for PTPmu-mediated neurite outgrowth and repulsion have been identified. Some of these signals are proteins that interact with, or bind, to PTPmu, whereas, others may be dephosphorylated by PTPmu. PTPmu interacts with the scaffolding proteins RACK1/GNB2L1, and IQGAP1. IQGAP1 is a scaffold for Rho family of GTPases, E-cadherin, beta-catenin and other proteins. IQGAP1 binding to Rho GTPases is necessary for PTPmu-mediated neurite outgrowth. The growing tip of the neuron, the growth cone, has a distinct appearance depending on what signals are activated inside the growth cone when it touches different substrates. The morphology of the growth cones on PTPmu and the repulsion of temporal neurites are both regulated by the Rho GTPase family member, Cdc42. Inhibition of the Rho GTPase Rac1 permitted neurite outgrowth on PTPmu from neurons in the temporal retina.

The proteins PLCγ1 (PLCG1), PKCδ (PRKCD) and BCCIP are PTPmu substrates. PKCδ activity is required for PTPmu mediated neurite outgrowth and PTPmu-mediated neurite repulsion. Expression of BCCIP is necessary for PTPmu-mediated neurite outgrowth. PTPmu is cleaved in certain brain cancers, which results in nuclear translocation of the cytoplasmic domain of PTPmu (see below). A possible function for the BCCIP-PTPmu interaction may be to shuttle the intracellular PTPmu fragment into the cell nucleus. In summary, PTPmu dephosphorylates PKCδ, PLCγ1, and BCCIP, and binds to IQGAP1. The expression and/or activity of all these proteins and Cdc42 is necessary for PTPmu-mediated neurite outgrowth. Also, the activity of the GTPase Rac1 promotes PTPmu-mediated neurite repulsion.