Potential Relation of Aberrant Proteolysis of Human Protein Tyrosine Kinase 7 (PTK7) chuzhoi by Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) to Congenital Defects

Vladislav S Golubkov,Alexander E Aleshin,Alex Y Strongin

doi:10.1074/jbc.m111.237669

Abstract

Membrane PTK7 pseudo-kinase plays an essential role in planar cell polarity and the non-canonical Wnt pathway in vertebrates. Recently, a new N-ethyl-N-nitrosourea-induced mutant named chuzhoi (chz) was isolated in mice. chz embryos have severe birth defects, including a defective neural tube, defective heart and lung development, and a shortened anterior-posterior body axis. The chz mutation was mapped to the Ala-Asn-Pro tripeptide insertion into the junction region between the fifth and the sixth Ig-like domains of PTK7. Unexpectedly, chz reduced membrane localization of the PTK7 protein. We hypothesized and then proved that the chz mutation caused an insertion of an additional membrane type 1 matrix metalloproteinase cleavage site in PTK7 and that the resulting aberrant proteolysis of chz affected the migratory parameters of the cells. It is likely that aberrations in the membrane type 1 matrix metalloproteinase/PTK7 axis are detrimental to cell movements that shape the body plan and that chz represents a novel model system for increasing our understanding of the role of proteolysis in developmental pathologies, including congenital defects.

Highlights

The canonical, ␤-catenin-dependent and non-canonical, ␤-catenin-independent Wnt signaling pathways are conserved in eukaryotes and are critical for the diverse events in embryonic development and disease
Expressed PTK7 pseudo-kinase is an essential component of the non-canonical Wnt/planar cell polarity (PCP) signaling pathway, arguably one of the most important cellular pathways in eukaryotes [46, 47]
At its most basic level, polarity may be considered as the generation of asymmetry within a single cell, whether the result of the asymmetry is a directed movement that leads to cellular migration or to the relocalization of specific multicellular structures

Summary

Introduction

The canonical, ␤-catenin-dependent and non-canonical, ␤-catenin-independent Wnt signaling pathways are conserved in eukaryotes and are critical for the diverse events in embryonic development and disease. 1 To whom correspondence should be addressed: Cancer Research Center, signaling events occur at a gastrulation stage of embryogenesis These events regulate the polarized directed cell movement to accomplish convergent extension for the anterior-posterior body axis elongation, neural tube closure, and craniofacial morphogenesis [3,4,5,6]. It is likely that PTK7 regulates PCP and signaling via homotypic interactions between the extracellular Ig domains and via the cytoplasmic PTK domain, respectively. PTK7 mutant mice that expressed either a 1–114 PTK7 truncation or a cytoplasmic domain deletion died because of severe defects in neural tube closure [10]. Chz mutant embryos have defective convergent extension, including a broadened midline, a shortened anterior-posterior body axis, abnormal cell polarity in the ear, and defective neural tube and heart and lung development.

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