TY - JOUR

T1 - Glucose-Regulated Protein 94 (GRP94)

T2 - A Novel Regulator of Insulin-Like Growth Factor Production

AU - Argon, Yair

AU - Bresson, Sophie E.

AU - Marzec, Michal T.

AU - Grimberg, Adda

PY - 2020

Y1 - 2020

N2 - Mammals have two insulin-like growth factors (IGF) that are key mediators of somatic growth, tissue differentiation, and cellular responses to stress. Thus, the mechanisms that regulate the bioavailability of IGFs are important in both normal and aberrant development. IGF-I levels are primarily controlled via the growth hormone-IGF axis, in response to nutritional status, and also reflect metabolic diseases and cancer. One mechanism that controls IGF bioavailablity is the binding of circulating IGF to a number of binding proteins that keep IGF in a stable, but receptor non-binding state. However, even before IGF is released from the cells that produce it, it undergoes an obligatory association with a ubiquitous chaperone protein, GRP94. This binding is required for secretion of a properly folded, mature IGF. This chapter reviews the known aspects of the interaction and highlights the specificity issues yet to be determined. The IGF-GRP94 interaction provides a potential novel mechanism of idiopathic short stature, involving the obligatory chaperone and not just IGF gene expression. It also provides a novel target for cancer treatment, as GRP94 activity can be either inhibited or enhanced.

AB - Mammals have two insulin-like growth factors (IGF) that are key mediators of somatic growth, tissue differentiation, and cellular responses to stress. Thus, the mechanisms that regulate the bioavailability of IGFs are important in both normal and aberrant development. IGF-I levels are primarily controlled via the growth hormone-IGF axis, in response to nutritional status, and also reflect metabolic diseases and cancer. One mechanism that controls IGF bioavailablity is the binding of circulating IGF to a number of binding proteins that keep IGF in a stable, but receptor non-binding state. However, even before IGF is released from the cells that produce it, it undergoes an obligatory association with a ubiquitous chaperone protein, GRP94. This binding is required for secretion of a properly folded, mature IGF. This chapter reviews the known aspects of the interaction and highlights the specificity issues yet to be determined. The IGF-GRP94 interaction provides a potential novel mechanism of idiopathic short stature, involving the obligatory chaperone and not just IGF gene expression. It also provides a novel target for cancer treatment, as GRP94 activity can be either inhibited or enhanced.

KW - glucose regulated protein (GRP) 94

KW - insulin-like growth factor

KW - obligate chaperone

KW - I IGF-I

KW - TOLL-LIKE RECEPTORS

KW - ENDOPLASMIC-RETICULUM

KW - CHAPERONE ACTIVITY

KW - REFERENCE VALUES

KW - SHORT STATURE

KW - C-ELEGANS

KW - BINDING

KW - HORMONE

KW - GP96

U2 - 10.3390/cells9081844

DO - 10.3390/cells9081844

M3 - Review

C2 - 32781621

VL - 9

JO - Cells

JF - Cells

SN - 2073-4409

IS - 8

M1 - 1844

ER -