Sortilin Is a Major Protein Component of Glut4-containing Vesicles

Lin, Bao-Zhen; Pilch, Paul F.; Kandror, Konstantin V.

doi:10.1074/jbc.272.39.24145

Cited by 104 publications

(94 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These protocols have resulted in the identification of numerous proteins such as VAMP2 (Cain et al, 1992) and sorting receptors such as M6PR (Kandror and Pilch, 1996) and sortillin (Lin et al, 1997;Morris et al, 1998) that one might expect to be involved in vesicular traffic. Importantly and as cited in the introduction, IRAP was also identified in this way as marker for GSV trafficking that is apparently more abundant than GLUT4 itself.…”

Section: Discussionmentioning

confidence: 99%

p115 Interacts with the GLUT4 Vesicle Protein, IRAP, and Plays a Critical Role in Insulin-stimulated GLUT4 Translocation

Hosaka

Brooks

Presman

et al. 2005

MBoC

Self Cite

View full text Add to dashboard Cite

Insulin-regulated aminopeptidase (IRAP) is an abundant cargo protein of Glut4 storage vesicles (GSVs) that traffics to and from the plasma membrane in response to insulin. We used the amino terminus cytoplasmic domain of IRAP, residues 1-109, as an affinity reagent to identify cytosolic proteins that might be involved in GSV trafficking. In this way, we identified p115, a peripheral membrane protein known to be involved in membrane trafficking. In murine adipocytes, we determined that p115 was localized to the perinuclear region by immunofluorescence and throughout the cell by fractionation. By immunofluorescence, p115 partially colocalizes with GLUT4 and IRAP in the perinuclear region of cultured fat cells. The amino terminus of p115 binds to IRAP and overexpression of a N-terminal construct results in its colocalization with GLUT4 throughout the cell. Insulin-stimulated GLUT4 translocation is completely inhibited under these conditions. Overexpression of p115 C-terminus has no significant effect on GLUT4 distribution and translocation. Finally, expression of the p115 N-terminus construct has no effect on the distribution and trafficking of GLUT1. These data suggest that p115 has an important and specific role in insulin-stimulated Glut4 translocation, probably by way of tethering insulin-sensitive Glut4 vesicles at an as yet unknown intracellular site. INTRODUCTIONInsulin normalizes blood glucose levels by mobilizing the muscle and adipocyte glucose transporter isoform, GLUT4, from intracellular storage vesicles and moving it to the plasma membrane (Simpson et al., 2001;Bryant et al., 2002). Various models of GLUT4 trafficking suggest that GLUT4 must exist in more than one intracellular compartment and the major insulin sensitive pool is localized to a compartment that is distinct from endosomal markers and is commonly referred to as glucose transporter storage vesicles (GSVs), or insulin responsive vesicle (IRVs). Despite the critical function of glucose transport in glucose homeostasis, many of the details by which adipocytes and muscle form a pathway of insulin-sensitive GLUT4 trafficking remain unknown. However, it is virtually certain that the major cargo proteins of GSVs must interact with a number of cytosolic and membrane proteins, such as adaptors and tethers, in order to be properly sorted and regulated by insulin.Insulin-responsive aminopeptidase (IRAP) was identified as an abundant cargo protein associated with GLUT4 vesicles that translocates in response to insulin in a manner seemingly identical to GLUT4 Mastick et al., 1994;Keller et al., 1995;Malide et al., 1997;Martin et al., 1997;Ross et al., 1997). In fact, it is more abundantly expressed in vesicles than the transporter (Kupriyanova et al., 2002). When the cytoplasmic N-terminus of IRAP was microinjected into 3T3-L1 adipocytes, GLUT4 was localized on the plasma membrane even in the basal state (Waters et al., 1997), suggesting IRAP can play a role in GSV movement/targeting. A chimeric protein containing the intracellular domain of IRAP and ...

show abstract

Section: Discussionmentioning

confidence: 99%

p115 Interacts with the GLUT4 Vesicle Protein, IRAP, and Plays a Critical Role in Insulin-stimulated GLUT4 Translocation

Hosaka

Brooks

Presman

et al. 2005

MBoC

Self Cite

View full text Add to dashboard Cite

show abstract

“…A function for sortilin in glucose metabolism had been noted early on when the receptor was identified as a major constituent of vesicle carrying the glucose transporter (Glut) 4 48,49 . Following insulin stimulation, Glut4 moves from intracellular storage vesicles to the cell surface to facilitate uptake of glucose in muscle and adipose tissues.…”

Section: Sortilin a Risk Factor For Hypercholesterolemia And Myocardmentioning

confidence: 99%

Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases

Schmidt

Willnow

2016

Atherosclerosis

View full text Add to dashboard Cite

VPS10P domain receptors are a unique class of sorting receptors that direct intracellular transport of target proteins in neurons and that play central roles in neurodegenerative processes. Surprisingly, genome-wide association studies now implicate the very same receptors in cardiovascular and metabolic disturbances. In this review, we discuss current findings that uncovered some of the molecular mechanisms whereby sorting receptors, such as SORLA, sortilin, and SORCS1 control homeostasis in cardiovascular and metabolic tissues, and how they promote hypercholesterolemia, atherosclerosis, obesity, and diabetes, when being altered.3

show abstract

“…The initial studies identified the insulin-responsive aminopeptidase (IRAP) (11,12) and the sorting receptor, sortilin (15,16), as major proteins components of GLUT4 vesicles that translocate to the cell surface in response to insulin. With the advent of mass spectrometry, numerous additional proteins were identified as constituents of GLUT4-rich vesicles, notably components of the vesicular trafficking machinery (17) such as Vamp2 (13) and motor proteins that might mediate vesicle movement (18) as well as additional cargo proteins such as the receptors for transferrin (TfR) (13) and cation-independent mannose 6-phosphate (CIM6PR) (13,18).…”

mentioning

confidence: 99%

Proteomic Analysis of GLUT4 Storage Vesicles Reveals LRP1 to Be an Important Vesicle Component and Target of Insulin Signaling

Jedrychowski

Gartner

Gygi

et al. 2010

Journal of Biological Chemistry

Self Cite

114

146

View full text Add to dashboard Cite

Insulin stimulates the translocation of intracellular GLUT4 to the plasma membrane where it functions in adipose and muscle tissue to clear glucose from circulation. The pathway and regulation of GLUT4 trafficking are complicated and incompletely understood and are likely to be contingent upon the various proteins other than GLUT4 that comprise and interact with GLUT4-containing vesicles. Moreover, not all GLUT4 intracellular pools are insulin-responsive as some represent precursor compartments, thus posing a biochemical challenge to the purification and characterization of their content. To address these issues, we immunodepleted precursor GLUT4-rich vesicles and then immunopurified GLUT4 storage vesicle (GSVs) from primary rat adipocytes and subjected them to semi-quantitative and quantitative proteomic analysis. The purified vesicles translocate to the cell surface almost completely in response to insulin, the expected behavior for bona fide GSVs. In total, over 100 proteins were identified, about 50 of which are novel in this experimental context. LRP1 (low density lipoprotein receptorrelated protein 1) was identified as a major constituent of GSVs, and we show it interacts with the lumenal domains of GLUT4 and other GSV constituents. Its cytoplasmic tail interacts with the insulin-signaling pathway target, AS160 (Akt substrate of 160 kDa). Depletion of LRP1 from 3T3-L1 adipocytes reduces GLUT4 expression and correspondingly results in decreased insulin-stimulated 2-[ 3 H]deoxyglucose uptake. Furthermore, adipose-specific LRP1 knock-out mice also exhibit decreased GLUT4 expression. These findings suggest LRP1 is an important component of GSVs, and its expression is needed for the formation of fully functional GSVs.The insulin-dependent translocation of GLUT4 from intracellular membranes to the cell surface is a well studied paradigm for the effects of signal transduction on membrane trafficking, and this process is of considerable physiological relevance for the regulation of glucose homeostasis, as dysregulation of this process plays a role in insulin resistance and type 2 diabetes mellitus (1). Only about half of the intracellular GLUT4 translocates to the plasma membrane in response to insulin (2-5) suggesting that more than one GLUT4-containing compartment exists. In addition, kinetic analyses of GLUT4 trafficking are consistent with the interpretation that GLUT4 traffics through multiple intracellular compartments (6 -8). These and other data have led to the concept that an ultimate target of insulin signaling is a subpopulation of translocating GLUT4-containing membranes that are commonly referred to as GLUT4 storage vesicles (GSVs) 3 (9, 10). The focus of many groups over the years has been on how these GSVs form, what their protein composition is, and how insulin communicates with them and stimulates their translocation to the cell surface.GLUT4-containing vesicles have been purified and their protein composition analyzed by a number of investigators, first by conventional protein sequencing (11, 12)...

show abstract

Sortilin Is a Major Protein Component of Glut4-containing Vesicles

Cited by 104 publications

References 22 publications

p115 Interacts with the GLUT4 Vesicle Protein, IRAP, and Plays a Critical Role in Insulin-stimulated GLUT4 Translocation

p115 Interacts with the GLUT4 Vesicle Protein, IRAP, and Plays a Critical Role in Insulin-stimulated GLUT4 Translocation

Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases

Proteomic Analysis of GLUT4 Storage Vesicles Reveals LRP1 to Be an Important Vesicle Component and Target of Insulin Signaling

Contact Info

Product

Resources

About