Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice

Abstract

Disabled-2 (Dab2) is a clathrin and cargo binding endocytic adaptor protein, and cell biology studies revealed that Dab2 plays a role in cellular trafficking of a number of transmembrane receptors and signaling proteins. A PTB/PID domain located in the N-terminus of Dab2 binds the NPXY motif(s) present at the cytoplasmic tails of certain transmembrane proteins/receptors. The membrane receptors reported to bind directly to Dab2 include LDL receptor and its family members LRP1 and LRP2 (megalin), growth factor receptors EGFR and FGFR, and the cell adhesion receptor beta1 integrin. Dab2 also serves as an adaptor in signaling pathways. Particularly, Dab2 facilitates the endocytosis of the Ras activating Grb2/Sos1 signaling complex, controls its disassembly, and thereby regulates the Ras/MAPK signaling pathway. Cellular analyses have suggested several diverse functions for the widely expressed proteins, and Dab2 is also considered a tumor suppressor, as loss or reduced expression is found in several cancer types. Dab2 null mutant mice were generated and investigated to determine if the findings from cellular studies might be important and relevant in intact animals. Dab2 conditional knockout mice mediated through a Sox2-Cre transgene have no obvious developmental defects and have a normal life span despite that the Dab2 protein is essentially absent in the mutant mice. The conditional knockout mice were grossly normal, though more recent investigation of the Dab2-deficient mice revealed several phenotypes, which can be accounted for by several previously suggested mechanisms. The studies of mutant mice established that Dab2 plays multiple physiological roles through its endocytic functions and modulation of signal pathways.

News on the molecular regulation and function of hepatic low-density lipoprotein receptor and LDLR-related protein 1

“…DAB2 mutations correlated with hypercholesterolemia have not been reported yet, and DAB2 deficient mice are not viable. In mice, DAB2 is likely important for normal development of the placenta as Dab2 knockout mice with only normal expression of Dab2 in extra-embryonic tissues are born alive [12]. These mice have a slight increase in circulating plasma cholesterol.…”

The ins and outs of endocytic trafficking in platelet functions

“…Disabled-2 (Dab2) is a clathrin- and cargo-binding adaptor protein that is involved in endocytic trafficking of many cell surface receptors and in modulating intracellular signaling [38]. Alternate splicing generates two isoforms, p82-Dab2 and p59-Dab2 [39].…”

Epstein-Barr virus miR-BART1-3p suppresses apoptosis and promotes migration of gastric carcinoma cells by targeting DAB2

“…Disabled homolog 2 (DAB2) encodes a mitogen-responsive phosphoprotein that contains a phosphotyrosine-binding domain and a proline-rich domain involved in the regulation of clathrinmediated endocytosis as well as receptor-mediated signaling pathways [16][17][18][19][20]. DAB2 has been considered as a putative tumor suppressor in NPC [21,22] as well as ovarian [23,24], breast [25][26][27], prostate [28], and lung carcinoma [29,30].…”