Insulin and Insulin-Like Growth Factors: the Paradox of Signaling Speciﬁcity

Growth Hormone & IGF Research 2002, 12, 81–83 doi:10.1054/ghir.2002.0264, available online at http://www.idealibrary.com on

COMMENTARY Insulin and insulin-like growth factors: the paradox of signaling speciﬁcity

Pierre De Meyts

Receptor Biology Laboratory, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark. Tel: +45 44 43 91 67; Fax: +45 44 43 80 00; E-mail: [email protected]

In a thoughtful and balanced review in this issue reviewed by Kim and Accili suggest that the two recep- of Growth Hormone & IGF Research, Kim and Accili tors do have an intrinsic ability to mediate at least some address the complex question of what mechanisms de- of the other’s functions. Comparison of the signaling termine the specificity of intracellular signaling by the specificities of the intracellular domains of the IR and insulin receptor (IR) and insulin-like growth factor-I IGF-IR using chimeric constructs have suggested that (IGF-I) receptor (IGF-IR) tyrosine kinases.1 Despite ex- the differences are quantitative rather than qualitative tensive structural homology in both the ligands and (See references 41–431). the receptors, and largely overlapping intracellular sig- It is clear, as the authors point out, that some fac- naling networks, the two receptors appear in vivo to tors “extrinsic” to the nature of the signaling cascades mediate distinct and only partially overlapping pat- may affect signaling specificity, such as kinetics of in- terns of physiological responses, as evidenced by the sulin and IGF-I secretion, IGF binding proteins, level markedly different phenotypes of homozygous knock- of receptor expression, spatial localization6 and kinet- out mice. The genetics suggests that IGF-IR is pri- ics/duration of intracellular signals,7 as well as devel- marily a growth promoter and the IR a metabolic opmental regulation. The role of the time factor (tran- regulator. sient vs sustained signaling) has been well documented However, in vitro experiments have shown that, in regarding the specificity of MAP kinase signaling8 a given cellular context, the IR can mediate mitogenic or the metabolic vs mitogenic properties of insulin responses and the IGF-IR metabolic responses. The IR analogues.7 for one thing mediates growth in response to IGF-II Among “intrinsic” elements that may confer sig- during a period of embryonic development.1 TheIRis naling specificity, the authors mention differences in a growth promoter in a T-cell lymphoma line devoid the catalytic activities of the two kinase domains of IGF-IRs and unresponsive to the IGFs.2 The trun- or structural/sequence differences in the receptor cated intracellular domain of the IR, like that of the C-terminal domains, differential interactions with IRS IGF-IR, fused to an avian sarcoma virus, had a strong (Insulin Receptor Substrate) molecules and recruitment transforming and tumorigenic activity in chick embryo of different signaling molecules (such as CEACAM- fibroblasts.3,4 Conversely, the IGF-IR was shown to me- 2/pp120 and MAD2 for IR and 14-3-3, Grb10, IIP-1 diate IGF-I and insulin’s metabolic effects on glucose and c-Crk for IGF-IR). As far as Grb10 is concerned, transport and glycogen synthase in fibroblasts5 and however, a recent study shows that its BPS do- myoblasts1 from IR knockout mice, although studies main inhibits the catalytic activity of both receptor in hepatocytes from the same mice have suggested kinases.9 As the authors point out, we know very little that different pathways may mediate the metabolic re- about the potential specificity of mechanisms of sig- sponses to insulin and IGF-I.1 These and other data nal termination. Scaffold proteins (e.g. those that bind

together selected partners among the multiple iso- sion level that could explain their different biological mers of the MAP kinase cascade) may also play an actions. important role in facilitating signal transduction by pre- Finally, as strongly suggested by the authors, the time forming multimolecular complexes that can be rapidly may be ripe to go back to an in vivo genetic approach to activated by incoming signal, thus regulating the speci- physiology by “knocking in” hypomorphic (i.e. with de- fivity, efficiency and amplitude of signal propagation.10 creased function or expression rather than total inacti- Other elements of specificity are discussed in another vation) mutated or chimeric alleles of receptors and/or recent review.11 signaling molecules in mice, as several recent success- It is clear that the currently available methodologies ful examples encourage us to try. (co-immunoprecipitation of usually overexpressed re- I also believe that in order to understand better ceptors/signaling molecules; two-hybrid systems) are the complexity and multidimensionality of what is in- inadequate to address the fine details of interac- creasingly called “combinatorial signaling”,16 it will be tions that take place at physiological concentrations necessary to develop new theoretical–mathematical and in different cell locations. A full understanding approaches to the modelling of integrated networks, of signaling specificity will require more subtle ap- including for example applications of logical switching proaches. theory and queuing theory. One of these may be the rapidly developing fluorescent resonance energy transfer technology based on using chimeric proteins made of receptors or signal- REFERENCES ing proteins fused to spectral variants of the green fluorescent protein (GFP)12 or bioluminescence res- 1. 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