Differential Roles of the Insulin and Insulin-like Growth Factor-I (IGF-I) Receptors in Response to Insulin and IGF-I

Insulin and insulin-like growth factor-I (IGF-I) receptors are highly homologous tyrosine kinase receptors that share many common steps in their signaling pathways and have ligands that can bind to either receptor with differing affinities. To define precisely the signaling specific to the insulin receptor (IR) or the IGF-I receptor, we have generated brown preadipocyte cell lines that lack either receptor (insulin receptor knockout (IRKO) or insulin-like growth factor receptor knockout (IGFRKO)). Control preadipocytes expressed fewer insulin receptors than IGF-I receptors (20,000 versus 60,000), but during differentiation, insulin receptor levels increased so that mature adipocytes expressed slightly more insulin receptors than IGF-I receptors (120,000 versus 100,000). In these cells, insulin stimulated IR homodimer phosphorylation, whereas IGF-I activated both IGF-I receptor homodimers and hybrid receptors. Insulin-stimulated IRS-1 phosphorylation was significantly impaired in IRKO cells but was surprisingly elevated in IGFRKO cells. IRS-2 phosphorylation was unchanged in either cell line upon insulin stimulation. IGF-I-dependent phosphorylation of IRS-1 and IRS-2 was ablated in IGFRKO cells but not in IRKO cells. In control cells, both insulin and IGF-I produced a dose-dependent increase in phosphorylated Akt and MAPK, although IGF-I elicited a stronger response at an equivalent dose. In IRKO cells, the insulin-dependent increase in phospho-Akt was completely abolished at the lowest dose and reached only 20% of the control stimulation at 10 nm. Most interestingly, the response to IGF-I was also impaired at low doses, suggesting that IR is required for both insulin- and IGF-I-dependent phosphorylation of Akt. Most surprisingly, insulin- or IGF-I-dependent phosphorylation of MAPK was unaltered in either receptor-deficient cell line. Taken together, these results indicate that the insulin and IGF-I receptors contribute distinct signals to common downstream components in response to both insulin and IGF-I. Insulin and insulin-like growth factor-I (IGF-I) receptors are highly homologous tyrosine kinase receptors that share many common steps in their signaling pathways and have ligands that can bind to either receptor with differing affinities. To define precisely the signaling specific to the insulin receptor (IR) or the IGF-I receptor, we have generated brown preadipocyte cell lines that lack either receptor (insulin receptor knockout (IRKO) or insulin-like growth factor receptor knockout (IGFRKO)). Control preadipocytes expressed fewer insulin receptors than IGF-I receptors (20,000 versus 60,000), but during differentiation, insulin receptor levels increased so that mature adipocytes expressed slightly more insulin receptors than IGF-I receptors (120,000 versus 100,000). In these cells, insulin stimulated IR homodimer phosphorylation, whereas IGF-I activated both IGF-I receptor homodimers and hybrid receptors. Insulin-stimulated IRS-1 phosphorylation was significantly impaired in IRKO cells but was surprisingly elevated in IGFRKO cells. IRS-2 phosphorylation was unchanged in either cell line upon insulin stimulation. IGF-I-dependent phosphorylation of IRS-1 and IRS-2 was ablated in IGFRKO cells but not in IRKO cells. In control cells, both insulin and IGF-I produced a dose-dependent increase in phosphorylated Akt and MAPK, although IGF-I elicited a stronger response at an equivalent dose. In IRKO cells, the insulin-dependent increase in phospho-Akt was completely abolished at the lowest dose and reached only 20% of the control stimulation at 10 nm. Most interestingly, the response to IGF-I was also impaired at low doses, suggesting that IR is required for both insulin- and IGF-I-dependent phosphorylation of Akt. Most surprisingly, insulin- or IGF-I-dependent phosphorylation of MAPK was unaltered in either receptor-deficient cell line. Taken together, these results indicate that the insulin and IGF-I receptors contribute distinct signals to common downstream components in response to both insulin and IGF-I. Insulin and insulin-like growth factors (IGF-I and IGF-II) 1The abbreviations used are: IGF, insulin-like growth factor; IR, insulin receptor; IGFR, type-I insulin-like growth factor receptor; IRKO, insulin receptor knockout; IGFRKO, insulin-like growth factor receptor knockout; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase. lead to an assortment of biological effects in insulin target cells such as adipocytes, hepatocytes, and myocytes. Insulin and IGF-I action is propagated by the insulin receptor (IR) and the IGF-I receptor (IGFR), which have similar heterodimeric α2β2 structures and belong to the family of receptor tyrosine kinases (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4619) Google Scholar). The analysis of the metabolic and mitogenic effects elicited by IR and IGFR in vivo is complicated by many factors. The two receptors are expressed on the surface of most cells, but their relative proportions vary in different tissues. Insulin and IGF-I are capable of binding to each other's receptors, although with a 100-fold lower affinity than that of its own cognate receptor (2Steele-Perkins G. Turner J. Edman J.C. Hari J. Pierce S.B. Stover C. Rutter W.J. Roth R.A. J. Biol. Chem. 1988; 263: 11486-11492Abstract Full Text PDF PubMed Google Scholar, 3Werner H. Woloschak M. Stannard B. Shen-Orr Z. Roberts Jr., C.T. LeRoith D. LeRoith D. Insulin-like Growth Factors. CRC Press, Boca Raton, FL1991: 17-47Google Scholar). In addition, individual αβ heterodimers from IR and IGF-IR can also combine to form disulfide-linked hybrid receptors, which can bind both insulin and IGF-I (4Soos M.A. Whittaker J. 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P.A. H. PubMed Scopus Google Scholar, B. K. E. J. D. J. PubMed Scopus Google Scholar). the are and and to J. A. Cell. Full Text PDF PubMed Scopus Google Scholar, D.J. Burks D.J. White M.F. Scopus Google Scholar). that IR is more in whereas IGFR growth and that receptor the receptor is to the signaling of the receptors have on the of or receptors in cells (2Steele-Perkins G. Turner J. Edman J.C. Hari J. Pierce S.B. Stover C. Rutter W.J. Roth R.A. J. Biol. Chem. 1988; 263: 11486-11492Abstract Full Text PDF PubMed Google Scholar, H. Stannard B. R. Roberts Jr., C.T. LeRoith D. J. Cell. PubMed Scopus Google Scholar, R. A. Schlessinger J. Ullrich A. J. PubMed Scopus Google Scholar, Soos M. J.M. Siddle K. S. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the of the receptors that with more levels of receptor the used in these not levels of insulin or IGF-I receptors a of to insulin or IGF-I with target tissues. is a form of in to brown is an that both insulin and IGF-I receptors M. Biochem. J. PubMed Scopus Google Scholar). a to brown cell lines from J. M. M. Kahn C.R. 2002; PubMed Scopus Google to the of signaling in In we have generated brown preadipocyte cell lines that lack either IR or IGFR and have and signaling in these receptor-deficient cells. that IR is required for brown whereas IGFR is and each receptor downstream signaling in distinct used for and receptor and receptor from and by receptor and and and from was from and from IGF-I was from from and that for a of the insulin receptor used as for also from for a of of the IGF-I receptor preadipocytes from control and by as J. M. M. M. Kahn C.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). by with a and with in with in a in of the insulin or IGF-I receptor, preadipocytes a of the insulin receptor or IGF-I receptor at a cells with an at a of of the was with for IR or IGFR using with J.C. C. M.A. Kahn C.R. Cell. Full Text Full Text PDF Scopus Google Scholar, M. G. B. L. M. PubMed Scopus Google Scholar). and cells, preadipocytes to in insulin and was by with with and for cells to which was cells mature with and with for at at for at with in with and in control and of IRKO cells, and IGFRKO cell preadipocytes in have the to their or of J. M. M. Kahn C.R. 2002; PubMed Scopus Google Scholar). cell lines in used to and have similar growth not that the mitogenic of these cells was also and of or IRKO cells the insulin receptor was Kahn C.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The of IGFR by was cells by with 10 of and Control or IGFRKO preadipocytes with for and in the and or binding have S. A. Kahn C.R. J. PubMed Scopus Google with the lines to and with and in of binding or with of the for at was in for each dose. with by two of with and was using a of was and cells using a The as the of to versus the of cell of the was to the binding affinity of the the dose for or was in cells IR or IGFR The as binding of the and in 10 10 10 and and by for and protein by the Biochem. PubMed Scopus Google Scholar). of cell of protein in and on was to and using the with the and with of protein was with the and protein for at the of IR or IGFR used for their by in in and as for phospho-Akt and on a and using Insulin and IGF-I for the of IR and IGFR in we have the of brown preadipocyte cell lines that lack or each of these receptors by homologous J.C. C. M.A. Kahn C.R. Cell. Full Text Full Text PDF Scopus Google Scholar, M. G. B. L. M. PubMed Scopus Google Scholar). lines the of IR or IGFR as (IRKO) and cell lines by of cells in as control and receptor-deficient cell lines by to cell lines that either IR or IGFR IGFRKO have that the insulin receptor that the expressed in brown preadipocytes Kahn C.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and we have used for the to by the of and and as mature adipocytes on of the in both control cell lines adipocytes as by of 10 of cells to that receptor was required for the cell lines for IGFR, to whereas the two the of IGFR in the by with an on protein during the of IGFR levels increased slightly in control cells at IGFR was not in of the IGFRKO to control cells, of receptor and two of differentiation, in IGFRKO and The that two cells capable of that IGFR was not for we have Kahn C.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google of IR to of IRKO cells, and of IR in control cells In of IGFR in control cells not that both the and these two receptors in the of Control and of cell lines to as the of differentiation, protein was and with the and with Insulin and IGF-I in and the effects of receptor we the levels of IR and IGFR in adipocytes and in the cell In control cells at the of preadipocytes expressed low levels of insulin receptor as by with an specific to the the of differentiation, IR was increased and its at in IGFR by for its although was a increase at the of and the relative protein levels of IR and IGFR in the cell the knockout cell lines we have on cells in the preadipocyte for IR was in IRKO cells and in cells IGFR was in IGFRKO cells but was highly elevated in cells was in insulin receptor levels in IGFRKO cells, and IGFR levels in IRKO cells similar to that in control cells. was receptor either receptor was To of either receptor hybrid receptor protein from preadipocyte cell lines with the of IR or IGFR, and with both IR and IGFR of IR by for IGFR that the same of IGFR was with IR in control cells and cells IR or IGFR similar of IR with IGFR in control cells and cells either IR or IGFR lower hybrid receptors in IRKO or IGFRKO cells. that a of hybrid receptors is and of IR or IGFR not significantly the of these hybrid receptors. the signaling in cells these receptors can to of IR or IGFR To more precisely the of receptors on the cell we insulin and IGF-I binding on control preadipocytes and mature adipocytes, as as on cells IR or of binding that insulin binding was low in preadipocytes which the low of IR in of the we that preadipocytes insulin receptors on their cell surface differentiation, adipocytes a increase in insulin binding and with an increase in IR to receptors as by In IRKO preadipocytes insulin receptors insulin binding was similar to that in control adipocytes with a receptor of and IGF-I receptor and binding affinity in brown in a IGF-I binding was than insulin binding in control preadipocytes the in with was in a of receptors, as by expressed on these cells differentiation, IGF-I binding was slightly increased with an increase in receptor to receptors cell increase in IGFR the in by IGFRKO IGFR preadipocytes expressed receptors, which was slightly than levels in control In both preadipocytes and adipocytes the affinity of the IGF-I receptor was than that of the insulin receptor versus binding to the of each to with the In binding to the insulin receptor, the for binding of by insulin and IGF-I was although IGF-I was by an of to the versus IGF-I was to binding with an of affinity receptors In only of insulin to IGF-I from IGFR was a but of binding of to IRKO the of insulin to bind IGF-I receptors on the low affinity of insulin for the IGFR, the of insulin to signaling was than on binding Insulin IR whereas IGF-I IGFR and receptor by the different cells stimulated with of insulin or IGF-I for 10 and protein with the of IR or IGFR and with a In control cells, insulin stimulated phosphorylation of IR at 10 and IGF-I phosphorylation of two that with to the IR and the to the IGFR The of the two an of receptor which that results from the of hybrid receptors. insulin IGF-I tyrosine phosphorylation of protein by an from IRKO cells. the phosphorylation of IR was slightly increased in IGFRKO cells, and in these cells, IGF-I was to phosphorylate In cells that IR, insulin levels of IR of the increased IR In these same cells, IGF-I was also to phosphorylation of IR and hybrid receptors as by the In IGFRKO cells IGFR, insulin- and phosphorylation of IR or similar to that in control cells. In control cells, insulin was only to tyrosine phosphorylation of IGFR in at that binding of insulin to the IGF-I receptors at of IGF-I was to phosphorylation of both IGFR and IR in the phosphorylation of IGFR was more than phosphorylation of IR, which the of IGFR as as the of hybrid receptors. In the of insulin receptors, only the of insulin was to IGFR IGF-I was only to phosphorylate IGFR in IRKO cells, and the of phosphorylation was similar to that in control cells for IGFR Insulin and IGF-I to phosphorylation of IGFR in IGFRKO cells. In cells IR, insulin was to phosphorylate hybrid receptors. IGF-I was also to phosphorylation of and IGFR homodimers in IRKO IR cells, although to a than in control cells. In IGFRKO cells IGFR, only insulin was to IGFR phosphorylation, and phosphorylation of IR was of the of receptors in these cells, IGF-I phosphorylation of IGFR homodimers at and of IRS-1 and IRS-2 on and IGF-I both phosphorylate and activate To either specific we stimulated the receptor-deficient and receptor cell lines with insulin or IGF-I and tyrosine phosphorylation of IRS-1 and which are the most proteins in these cells K. E. Kahn C.R. Cell. Biol. PubMed Scopus Google Scholar). the protein IRS-1 was elevated in IRKO cells relative to control cells increased was in cells The levels of on the unaltered in IGFRKO cells either in the or of IRS-2 levels similar in cell In control cells, both insulin and IGF-I elicited a dose-dependent increase in tyrosine phosphorylation of although IGF-I was more than insulin in the relative levels of IR and IGFR expressed on these cells as as the affinity of IGF-I as with insulin for their cognate receptors The tyrosine phosphorylation of IRS-1 at IGF-I was similar to that with 10 these elevated IRS-1 protein IRS-1 phosphorylation was in IRKO cells, although the was to phosphorylation of by IGFR phosphorylation of IRS-1 was unaltered in IRKO cells. In IGFRKO cells, phosphorylation of IRS-1 was suggesting that IGFR IR signaling to phosphorylation of IRS-1 by IGF-I was impaired in IGFRKO cells, although IGF-I phosphorylation of with In cells either IR or IGFR, both insulin and IGF-I to phosphorylation of IRS-1 phosphorylation in IRKO IR cells by the elevated IRS-1 In control cells, equivalent of insulin and IGF-I similar levels of IRS-2 phosphorylation phosphorylation was unaltered in IRKO cells, suggesting that insulin can the IGFR to In IGFRKO cells, although phosphorylation of IRS-2 was not phosphorylation of IRS-2 was that IGFR was required for Insulin-stimulated IRS-2 phosphorylation was elevated in cells the response to IGF-I was similar to control cells. that IGF-I-dependent phosphorylation of IRS-2 required Most surprisingly, phosphorylation of IRS-2 by insulin or IGF-I was in cells IGFR, suggesting by of IR and IGFR of Akt but proteins proteins that signaling Akt and MAPK are two which are downstream of and are activated by both insulin and IGF-I. we the phosphorylation of Akt and MAPK by using to these levels of Akt and MAPK protein similar in cell lines not with insulin in a dose-dependent increase in Akt phosphorylation in control cells response to insulin was abolished in IRKO cells at 10 and significantly at nm. In IGFRKO cells, Akt phosphorylation was although not these that IGFR IR of Akt. of IR elevated Akt phosphorylation with a stimulation at 10 which was than that at in control cells. Insulin-stimulated phosphorylation of Akt was also increased in cells IGFR, although the dose response was to the with cells IGF-I also a dose-dependent increase in Akt phosphorylation in control cells, with a response at 10 that IGF-I a phosphorylation of Akt than and the that are more IGF-I receptors in these cells with insulin receptors Most surprisingly Akt phosphorylation was impaired in IRKO cells at and 10 although at the was not the that IGFR levels are unaltered in these cells. In IGFRKO cells, phosphorylation of Akt by IGF-I was although was only at nm. IGF-I-dependent phosphorylation of Akt at required both IGF-I and insulin receptors, we that response a hybrid IGF-I Akt phosphorylation was unaltered in cells in cells IGFR, Akt phosphorylation was increased with IGF-I but unaltered at the response at 10 reached stimulation. of MAPK by insulin or IGF-I a different than Akt. In control cells insulin a dose-dependent increase in MAPK phosphorylation In IRKO cells, response was although not that insulin IGFR to The dose response in IGFRKO cells was MAPK phosphorylation was elevated in cells IR with an Most surprisingly, of IGFR impaired phosphorylation of MAPK, that IGFR IR IGF-I also elicited MAPK phosphorylation in a dose-dependent in control cells response was only slightly elevated with insulin stimulation. MAPK phosphorylation was unchanged in either IRKO or IGFRKO cells, suggesting that the of either receptor was for of either IR or IGFR not MAPK phosphorylation by IGF-I. Insulin and IGF-I receptors are similar and activate many of the same signaling IR and IGFR are expressed in the same cells, is to the of insulin and IGF-I these ligands can bind either receptor, although with a lower affinity than their cognate To complicate matters further, individual αβ heterodimers from IR and IGFR can combine to form hybrid receptors, which as IGF-I receptors but can also bind insulin (4Soos M.A. Whittaker J. Lammers R. Ullrich A. Siddle K. Biochem. J. 1990; 270: 383-390Crossref PubMed Scopus (168) Google Scholar, 6Pandini G. Frasca F. Mineo R. Sciacca L. Vigneri R. Belfiore A. J. Biol. Chem. 2002; 277: 39684-39695Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar). To the individual of IR and IGFR to signaling and hybrid receptor we have brown preadipocyte cell lines either receptor, IRKO or have on the of on receptor-deficient cell IGF-I on B. A. C.T. J. D. PubMed Scopus Google or insulin on cells C. Kahn C.R. M. 2002; PubMed Scopus Google Scholar, C. M. M. PubMed Scopus Google Scholar). the of both insulin and IGF-I on and cell lines that by similar brown preadipocyte cell lines from with of in the signaling to define similar brown preadipocytes IRS-1 to mature adipocytes and impaired M. J. K. M. Kahn C.R. Cell. Biol. PubMed Scopus Google Scholar, Kahn C.R. M. PubMed Scopus Google Scholar). adipocytes only in but and M. J. K. M. White M.F. Kahn C.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Kahn C.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google we have that the insulin receptor was required for of brown preadipocytes in In we have that IGFR is not required for of brown which is that preadipocytes more IGFR than of is in brown adipocytes from C. M. M. PubMed Scopus Google Scholar). that both IR and IGFR have in that for by signaling the Most surprisingly, to similar levels in control preadipocytes the IR whereas IGFR that different signals from the receptors to similar of the individual for IR and IGFR in can also in both insulin and IGF-I receptors and to either during E. M. M. S. J. Full Text Full Text PDF PubMed Scopus Google Scholar). from IRKO to as by the of and E. M. M. D. S. G. PubMed Scopus Google Scholar). elevated of to in in as by increased and of the J. A. Cell. Full Text PDF PubMed Scopus Google Scholar). In are more IGFR than IR, IGFR the receptor in these cells. is not that IGF-I is more than insulin in downstream such as IRS-1 and Akt. IGF-I receptors are not for brown or the of biological the of these receptors with their ligands with the of the to binding at doses, we have a of IR and IGFR signaling by on elicited by levels of to the of results is that factors not the of stimulation in different cell or with different in the or of the or the of the of these we have on the of insulin or IGF-I to activate signals in the receptor-deficient cell lines of the of the signals In these cells, insulin to and the insulin receptor but not to activate hybrid receptors The phosphorylation of both IRS-1 and Akt is on the of insulin with its cognate the phosphorylation of IRS-2 and MAPK in the of insulin receptors, that insulin binding to IGFR can the of these signals IGF-I to and IGFR homodimers as as hybrid receptors IGF-I stimulation of both IRS-1 and IRS-2 the of IGFR, although not the that hybrid receptors also in these is that hybrid receptors are for IGF-I of Akt phosphorylation not either IGFR or IR is MAPK phosphorylation in either receptor-deficient cell line is equivalent to that in suggesting that IGF-I either receptor with to activate is to Akt or MAPK is to specific protein both insulin and IGF-I are capable of IRS-1 and that can is that in IRKO cells of insulin are capable of phosphorylation of IRS-2 and MAPK but not IRS-1 or Akt. at is not capable of phosphorylation of IRS-2 in IGFRKO cells, although stimulation of Akt phosphorylation that stimulation of Akt by either is more to IRS-1 phosphorylation, whereas MAPK is downstream of either protein or not signaling in the receptor-deficient cell we can the of that in these cells. IGF-I is to the IR in IGFRKO and these signaling the binding of IGF-I for the insulin insulin the IGFR to downstream signals in IRKO cells, the are than on its low binding insulin the IGFR a than IGF-I to also in insulin stimulation of IGFR phosphorylation can at of insulin IGFR is not to IGF-I binding F. Kahn C.R. R. A.C. White M.F. Biochemistry. 1988; PubMed Scopus Google Scholar). B. A. C.T. J. D. PubMed Scopus Google have that are to insulin at in the of receptor, the can as an receptor to the biological effects of either In the IRKO preadipocytes in which we have IR, insulin receptor levels in mature adipocytes, than levels in preadipocyte cells. have that of IR in the preadipocyte the of IR and IGFR signaling that required for Kahn C.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In these cells, hybrid receptor is that the signals from IR or IGFR with preadipocytes that IR, the increase in IGFR is in IGFRKO IGFR cells, but the IGF-I receptor is that in control increase in IGFR levels also the of IR and IGFR of IR in IRKO cells phosphorylation of IGFR whereas of IGFR in IGFRKO cells IGFR homodimer signaling to the of hybrid insulin and IGF-I activate both IR and IGFR that cells a of receptors to biological such as In IRKO cells IRS-1 levels are elevated relative to control cells, and the of insulin in IRS-1 levels and for of signaling in these cells. In of of IR in IRKO cells IRS-1 we not in IRS-1 levels in IGFRKO cells. by C. Kahn C.R. M. 2002; PubMed Scopus Google Scholar, C. M. M. PubMed Scopus Google IRS-1 levels in their of IGFR for in the cell used in these have on the in adipocytes, and the of the cells IRS-1 In during of brown adipocytes, IRS-1 levels are at the but as cells mature adipocytes K. E. Kahn C.R. Cell. Biol. PubMed Scopus Google Scholar). is in IRS-1 levels in IGFRKO cells, IRS-1 tyrosine phosphorylation is that IGFR IR In addition, Akt phosphorylation is also elevated in IGFRKO cells, although not MAPK phosphorylation by insulin is in cells the of IGFR with insulin in these cells. brown is for and the for brown in of brown in results in with and insulin A. J. Nature. PubMed Scopus Google Scholar, A. H. 1995; PubMed Scopus Google Scholar). the these also insulin in both and similar is in with a knockout of the insulin receptor in brown C. M. J. Kahn C.R. M. J. PubMed Google Scholar). these are with brown is an in brown which results from a in both cell and of these with as a of impaired insulin the of the insulin receptor in an such as brown can In although insulin and IGF-I have to activate similar signaling and are not In the of brown differentiation, of IR, which is expressed at low whereas of the IGFR, which is suggesting that these homologous receptors have different in receptor increase the of tyrosine kinase which in lead to an elevated signaling that receptor is not as as the of IR and IGFR levels in a In the have to the and of insulin and IGF-I receptors and to with