Endocytic adaptors Arh and Dab2 control homeostasis of circulatory cholesterol

Tao, Wensi; Moore, Robert H.; Meng, Yue; Smith, Elizabeth; Xu, Xiang Xi

doi:10.1194/jlr.m063065

Cited by 27 publications

(28 citation statements)

References 32 publications

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“…The Dab2 null mice appear mostly normal, though we observed a slight increase in serum cholesterol2030, which is consistent with the role of Dab2 as an endocytic adaptor for the LDL receptor31. To investigate further the importance of Dab2 in LDL metabolism, we challenged the Dab2 null ( dab2 (fl/df);Sox2-Cre) mice with a high fat diet.…”

Section: Resultssupporting

confidence: 81%

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Disabled-2 Determines Commitment of a Pre-adipocyte Population in Juvenile Mice

Tao

Moore

Meng

et al. 2016

Sci Rep

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Disabled-2 (Dab2) is a widely expressed clathrin binding endocytic adaptor protein and known for the endocytosis of the low-density lipoprotein (LDL) family receptors. Dab2 also modulates endosomal Ras/MAPK (Erk1/2) activity by regulating the disassembly of Grb2/Sos1 complexes associated with clathrin-coated vesicles. We found that the most prominent phenotype of Dab2 knockout mice was their striking lean body composition under a high fat and high caloric diet, although the weight of the mutant mice was indistinguishable from wild-type littermates on a regular chow. The remarkable difference in resistance to high caloric diet-induced weight gain of the dab2-deleted mice was presented only in juvenile but not in mature mice. Investigation using Dab2-deficient embryonic fibroblasts and mesenchymal stromal cells indicated that Dab2 promoted adipogenic differentiation by modulation of MAPK (Erk1/2) activity, which otherwise suppresses adipogenesis through the phosphorylation of PPARγ. The results suggest that Dab2 is required for the excessive calorie-induced differentiation of an adipocyte progenitor cell population that is present in juvenile but depleted in mature animals. The finding provides evidence for a limited pre-adipocyte population in juvenile mammals and the requirement of Dab2 in the regulation of Ras/MAPK signal in the commitment of the precursor cells to adipose tissues.

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Section: Resultssupporting

confidence: 81%

“…To investigate further the importance of Dab2 in LDL metabolism, we challenged the Dab2 null ( dab2 (fl/df);Sox2-Cre) mice with a high fat diet. However, only small perturbation in serum cholesterol level was observed, suggesting a redundant role of additional LDL receptor adaptor such as Arh3032.…”

Section: Resultsmentioning

confidence: 95%

Disabled-2 Determines Commitment of a Pre-adipocyte Population in Juvenile Mice

Tao

Moore

Meng

et al. 2016

Sci Rep

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“…However, in the absence of Arh, the additional loss of Dab2 greatly augments serum LDL and cholesterol levels to an extent similar to that observed in LDL receptor null mice (Tao et al, 2016a). The finding leads to the conclusion that Dab2 does not cooperate but complements Arh in LDL receptor endocytosis in the clearance of serum LDL particles.…”

Section: Function In Ldl Uptake and Cholesterol Homeostasissupporting

confidence: 53%

“…Dab2 protein sequences are also similar to other signal or endocytosis adaptor proteins including numb, numbl, and Arh protein (Figure 1). Compensatory expression and partial functional redundancy by numb and Arh have been noted in Dab2 knockout mice (Moore et al, 2013; Tao et al, 2014, 2016a). …”

Section: Dab2 As An Endocytosis Adaptormentioning

confidence: 99%

Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice

Tao

Moore

Smith

et al. 2016

Front. Cell Dev. Biol.

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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.

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“…Another endocytic clathrin adaptor protein, Disabled-2 (Dab2), may also act as an LDLR-selective adaptor. The activity and ability of Dab2 to mediate LDLR endocytosis have been demonstrated in cultured cells and this may be another site of mutation which can contribute to ARH [6].…”

Section: Genetics and Mechanismmentioning

confidence: 99%

Autosomal Recessive Hypercholesterolemia: A Rare Cause of Familial Hypercholesterolemia

Kosmas¹

2017

BJSTR

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Endocytic adaptors Arh and Dab2 control homeostasis of circulatory cholesterol

Cited by 27 publications

References 32 publications

Disabled-2 Determines Commitment of a Pre-adipocyte Population in Juvenile Mice

Disabled-2 Determines Commitment of a Pre-adipocyte Population in Juvenile Mice

Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice

Autosomal Recessive Hypercholesterolemia: A Rare Cause of Familial Hypercholesterolemia

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