Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2006) 12 OC8

SFE2006 Oral Communications Young Endocrinologist prize session (8 abstracts)

Caveolin-1: A regulator of the IGFIR/Akt pathway mediating cellular proliferation but not survival

LC Matthews 1 , MJ Taggart 2 & M Westwood 2


1Endocrine Sciences, University of Manchester, Manchester, United Kingdom; 2Maternal and Fetal Health Research Centre, University of Manchester, Manchester, United Kingdom.


The insulin-like growth factors (IGFs) signal through the type 1 IGF receptor (IGFIR) to regulate cellular proliferation and survival. A current theory suggests that a subset of plasmalemmal lipid rafts, termed caveolae, may orchestrate such IGF-mediated signalling.

In order to investigate the role of caveolae and the marker protein caveolin in controlling IGF signals, two cell models of caveolin deficiency were generated. Using shRNA, caveolin-1 expression by 3T3L1 cells was downregulated (80% reduction by immunoblot) and clonal fibroblast cell lines were established from wildtype and caveolin-1 knockout mice. In these cell systems, IGF-dependent changes in proliferation, survival and activation of intracellular signalling proteins were assessed by thymidine incorporation, chromatin fragmentation and phospho-immunoblot respectively. Neither the downregulation nor knockout of caveolin-1 significantly altered the ability of 5 nM IGF-I to promote cellular survival. However, in vitro downregulation of caveolin-1 promoted a hyperproliferative response to 5 nM IGF-I (control3T3L1 4.3±0.2-fold; shRNA3T3L1 12.4±0.4-fold induction, n=4, P<0.01), despite no change in the expression or activation of IGFIR, IRS-1, Akt or p42/44 MAPK. In contrast, in vivo knockout of caveolin resulted in clonal fibroblasts with unaltered rates of IGF-dependent proliferation, even though the expression and activation of IGFIR, IRS-1 and Akt were clearly altered. Immunoprecipitation studies further demonstrated that in caveolin-containing cells, IGF interacts with the Akt1 isoform of Akt; expression of this isoform was reduced in the caveolin-1 knockout cells, but not the downregulated, cells. In summary, short-term downregulation of caveolin promotes a hyperproliferative response to IGF; however, cells with long-term knockout of caveolin revert to appropriate proliferative responses through compensatory changes in the expression of Akt isoforms. This data posits an IGFIR/caveolin/Akt pathway as an important component of the IGF signalling modulus regulating cellular proliferation with implications for diseases, such as cancers, in which caveolin expression is abnormal.

Volume 12

197th Meeting of the Society for Endocrinology

Society for Endocrinology 

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