The Conserved Immunoglobulin Domain Controls the Subcellular Localization of the Homophilic Adhesion Receptor Protein-tyrosine Phosphatase μ

Abstract

The receptor protein-tyrosine phosphatase (PTP) is a homophilic adhesion protein thought to regulate cell-cell adhesion in the vascular endothelium through dephosphorylation of cell junction proteins. In subconfluent cell cultures, PTP resides in an intracellular membrane pool; however, as culture density increases and cell contacts form, the phosphatase localizes to sites of cell-cell contact, and its expression level increases. These characteristics of PTP, which are consistent with a role in cell-cell adhesion, suggest that control of subcellular localization is an important mechanism to regulate the function of this phosphatase. To gain a better understanding of how PTP is regulated, we ex- The physical interactions of individual cells with the local environment is critical to the control of their growth, differentiation, and fate within a multicellular organism. These responses are initiated by cell adhesion receptors, which bind either homophilic or heterophilic ligands on apposing cells or the extracellular matrix. A critical aspect in the cellular response to these interactions is reversible protein tyrosine phosphorylation of cell junction-associated proteins (1, 2). In fact, the bulk of the tyrosine-phosphorylated cellular proteins are localized to sites of cell-cell and cell-extracellular matrix adhesion. Several protein-tyrosine kinases and phosphatases have been implicated in the regulation of cell adhesion (3-6). In particular, receptor protein-tyrosine phosphatases (RPTPs),

Structure of a Tyrosine Phosphatase Adhesive Interaction Reveals a Spacer-Clamp Mechanism

“…Type IIB receptor protein tyrosine phosphatases (RPTPs) combine cell adhesive and catalytic activities in one molecule (3) and hence are ideally equipped to act as initial sensors in phosphorylation-based signaling events. Homophilic (trans) interactions control the RPTP subcellular localization (4,5) and are believed to modulate signaling, but a mechanistic understanding of this process has been lacking.…”

Productive Folding of Tyrosinase Ectodomain Is Controlled by the Transmembrane Anchor

“…In the next construct, pTriEx-1.1-ST_Mu, the tyrosinase TMD was replaced with the TMD of receptor-like protein tyrosine phosphatase Mu (RPTPaseMu), which is known to localize to the plasma membrane (11). Another construct (pTriEx-1.1-ST_E2) was designed in which the ectodomain was attached to the TMD of the HCV E2 protein, which was reported to contain ER retention signals (12).…”

Receptor protein tyrosine phosphatase μ: measuring where to stick

“…The perpendicular orientation of RPTPμ to the cell surface is not absolute: it is expected that a certain degree of variation will be allowed by the apparently flexible juxtamembrane region (as also proposed for cadherins [32]). Nevertheless, the free diffusion of RPTPμ is restricted further by the ectodomain size, since it cannot access narrow intercellular spacings such as the tight junctions [37]. Further interactions between RPTPμ molecules, as well as between cadherins, probably in cis, have been proposed [19,21,27] (indicated here by arrows and question marks) but these remain to be confirmed by structural studies.…”