Review Article Integrative Molecular Medicine Volume 3(3): 666-671 Integr Mol Med, 2016 doi: 10.15761/IMM.1000220 ISSN: 2056-6360 Cadherin/catenin signaling in developmental biology and pathology Zen Kouchi* Department of Pathology, Institute for Developmental Research, Aichi Human Service Center, Japan Abstract he cadherin/catenin complex regulates diverse signaling pathways through cell-cell interaction in development, diferentiation, and ischemia and neurodegenerative disorders such as Alzheimer’s disease (AD). Several stimuli afecting cadherin-mediated signaling regulate the processing of membrane-spanning proteins, including amyloid precursor protein (APP), downregulate wnt-related signaling, or promote nuclear transcriptional program. Nuclear phosphoinositide signaling regulates stress- mediated chromatin modiication and contributes to the development of cell polarity or malignancy in cancers. Interestingly, the vascular endothelial (VE)-cadherin/ catenin complex can modulate the endothelial barrier function and blood vessel stability under inlammatory conditions provoked by hypoxia or stroke. Blood-brain barrier (BBB) permeability and the availability of nutrients are perquisites for normal brain functions. Occurrence of stroke, hypoxia-ischemia encephalopathy disrupts the homeostasis regulated by VE-cadherin/vascular endothelial growth factor (VEGF) receptor signaling, a process that difers between adult and neonatal brains. N-cadherin and VEGF regulate the angiogenesis or vascular response and recruitment or migration of neural progenitor cells to demyelinated lesions. he hypoxia-inducible factor (HIF) signaling axis activates key molecules such as netrin-1 and wnt-mediated catenin signaling in endothelial cells and oligodendrocyte precursor cells (OPCs) in the subventricular zone (SVZ) or subcortical white matter tract, and spatiotemporal dysregulation of HIF signaling may be the primary cause of periventricular leukomalacia. In this review, we discuss the cadherin/catenin-mediated machinery and relevant associated pathological disorders, focusing on the organization of the complicated molecular framework as well as on several developmental functions mediated by cadherin/catenin complex. Introduction Cadherin/catenin cell adhesion complexes are necessary for synaptogenesis, plasticity, endothelial survival, and vascular morphogenesis [1,2]. hese cell adhesion machineries are regulated by several catenins, including α-, β-, and δ-, or p120 catenins possessing armadillo (Arm) repeats in their central domains. α-Catenin interacts with several actin-binding proteins such as α-actinin and modulates the dynamics of actin cytoskeletons. Its interacting partner, β-catenin, constitutes the cadherin-mediated adherens junctions through the interaction with classical E- or N-cadherins [3]. β-Catenin also regulates synaptic homeostasis through binding to PDZ-domain- containing proteins, and modulates the neuronal activity or dendritic morphogenesis in neurons [4]. p120 catenin binds classical cadherins through their juxtamembrane (JMD) sequences and regulates their processing by presenilin-1 (PS1) [5,6]. Both p120 catenins and the armadillo repeat protein deleted in velo-cardio-facial syndrome (ARVCF) subfamily can exist as two major splicing isoforms that difer by the presence (isoform 1) or absence (isoform 3) of a coiled-coil region at the N-terminus, and regulate the classical cadherin transport and stability in the plasma membrane [7]. Interestingly, delta- interacting protein A (DIPA) was identiied as an isoform 1-speciic p120 binding protein. Both knockdown and overexpression of DIPA cause phenotypes similar to those seen in N-cadherin mutants, referred to hydrocephalus and heterotopia, which are implicated in aberrant cadherin-mediated signaling during brain development [8]. Furthermore, p120 catenin is involved in PS1-mediated cadherin processing, which could compete with APP cleavage organized by the γ-secretase complex in a context-dependent manner [6]. In addition, nuclear phosphatidylinositol-4,5-bisphosphate [PI[4,5] P2]-mediated signaling is necessary for the regulation of transcription and promotes E-cadherin biogenesis or suppresses inhibitor of growth protein 2 (ING2)-mediated chromatin remodeling in response to several stimuli [9]. Under hypoxic conditions, HIF-1 is stabilized by suppression of proteasomal degradation of its subunit HIF-1α, and both PS1 and PS2 are known to regulate the HIF-1α turnover [10]. PS1 and PS2 promote hypoxia-dependent HIF-1α expression, which is dependent on APP or its intracellular domain (AICD) generation by γ-secretase. On the other hand, HIF-1 signaling is responsible for the upregulation of vascular endothelial growth factor (VEGF) detected in cerebral infarction ater middle cerebral artery occlusion (MCAO) or neonatal stroke, and VE-cadherin is required for VEGF-mediated angiogenesis [1,11]. VEGF controls endothelial permeability by stimulating the β-arrestin- dependent endocytosis of VE-cadherin [12]. Interestingly, disruption of BBB function ater ischemic stroke difers among neonates and adults. In fact, expression of tight junction proteins is retained to a great extent in the immature brain than in the adult brain ater the stroke, and several genes that increase vascular permeability, such as that encoding VEGF receptor 2, are overexpressed only in the adult brain [13,14]. Correspondence to: Zen Kouchi, Department of Pathology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya-cho, Kasugai-city, Aichi 480-0392, Japan, Tel: +81-568-88-0811; Fax: +81-568-88- 0829; E-mail: zkouchi@inst-hsc.jp Key words: cadherin, hypoxia, p120 catenin, periventricular leukomalacia, presenilin Received: May 09, 2016; Accepted: May 23, 2016; Published: May 27, 2016