IGF-1 / JAK2-STAT5 Signaling Axis

Insulin-like growth factor 1 (IGF-1) is a 70-amino-acid single-chain polypeptide secreted primarily by hepatocytes in response to growth hormone (GH) and is the principal endocrine effector of the GH axis. It activates a heterotetrameric receptor tyrosine kinase, IGF1R, that distributes signaling across three major intracellular branches: the PI3K/AKT/mTOR cascade driving protein synthesis and cell survival, the MAPK/ERK cascade driving proliferation and gene expression, and a JAK2-STAT5 transcriptional arm that parallels the canonical GH receptor signaling network. The integrated output of these branches controls somatic growth, skeletal muscle mass, adipose tissue remodeling, glucose homeostasis, and tissue repair across virtually every organ system.

Pathway Components

The IGF-1 Ligand

IGF-1 is encoded by the IGF1 gene (human chromosome 12q23.2, UniProt P05019) as a 153-amino-acid prepropeptide; mature IGF-1 comprises residues 49-118 after signal peptide removal and C-domain cleavage. Structurally it belongs to the insulin superfamily, sharing approximately 50% sequence identity with insulin and an analogous A-B-C-D domain topology stabilized by three disulfide bridges.

The liver is the dominant source of circulating IGF-1: hepatocyte IGF1 transcription is driven by GH signaling through the GH receptor (GHR, GHR, UniProt P10912) and its coupled JAK2-STAT5 cascade. IGF-1 is also produced locally in muscle, bone, cartilage, kidney, and brain, where it acts in autocrine and paracrine modes independent of circulating levels.

Approximately 99% of circulating IGF-1 is bound to one of six IGF-binding proteins (IGFBP-1 through IGFBP-6, encoded by IGFBP1-6). The dominant ternary complex in plasma is a 150 kDa heterotrimer of IGF-1, IGFBP-3 (UniProt P17936), and the acid-labile subunit (ALS, IGFALS, UniProt P35858). This complex extends the serum half-life of IGF-1 from minutes (free form) to approximately 12-15 hours and serves as a circulating reservoir. Proteolytic cleavage of IGFBP-3 by serine proteases and matrix metalloproteinases releases bioavailable IGF-1 at target tissues. (PMID 25431053)

A second endogenous ligand, IGF-2 (IGF2, UniProt P01344), shares IGF1R binding capacity with lower affinity than IGF-1 at most receptor subtypes and is the dominant fetal growth factor before IGF-1 production is established postnatally.

IGF1R: The IGF-1 Receptor

The type 1 insulin-like growth factor receptor (IGF1R) is encoded by the IGF1R gene (human chromosome 15q26.3, UniProt P08069). It is a receptor tyrosine kinase (RTK) of the insulin receptor superfamily. The mature receptor is a disulfide-linked heterotetrameric complex: two extracellular alpha-subunits (each 706 residues), which form the ligand-binding domain, are covalently linked to two transmembrane beta-subunits (each 627 residues), which carry the intracellular kinase domain. This alpha-2 beta-2 architecture is held together by interchain disulfide bonds between the alpha subunits and between each alpha and the corresponding beta subunit.

The extracellular alpha-subunit contains the L1 domain (leucine-rich repeat) and cysteine-rich region, which together form the primary IGF-1 binding site. Binding of a single IGF-1 molecule induces a conformational change that promotes transphosphorylation of the two beta-subunit kinase domains. The primary activation phosphorylation sites are Tyr1158, Tyr1162, and Tyr1163 in the activation loop of the kinase domain; phosphorylation of all three dramatically increases catalytic activity toward downstream substrates. (PMID 17245430)

IGF1R shares high structural and sequence similarity with the insulin receptor (IR, INSR, UniProt P06213), which governs glucose metabolism. Hybrid receptors consisting of one IGF1R alpha/beta hemireceptor and one IR alpha/beta hemireceptor form in cells co-expressing both receptors and respond to both IGF-1 and insulin, though with distinct ligand affinities. This structural relationship explains the partial overlap between insulin and IGF-1 signaling and the propensity of supraphysiological IGF-1 to produce hypoglycemia through IR engagement.

The IGF-2/mannose-6-phosphate receptor (IGF2R, IGF2R, UniProt P11717) serves primarily as a clearance receptor, internalizing IGF-2 (and to a minor extent IGF-1) for lysosomal degradation without intrinsic signaling capacity. IGF2R expression thus modulates the bioavailability of ligands for IGF1R.

Adapter Proteins: IRS-1 and IRS-2

Following IGF1R activation, the receptor phosphorylates insulin receptor substrate 1 (IRS-1, IRS1, UniProt P35568) and IRS-2 (IRS2, UniProt Q9Y4H2) at multiple tyrosine residues. These adapter proteins have no intrinsic enzymatic activity but serve as docking scaffolds that recruit and organize downstream effectors through their Src homology 2 (SH2) domains and pleckstrin homology (PH) domains.

Phosphorylated IRS-1/2 recruit the p85 regulatory subunit of PI3K (encoded by PIK3R1, UniProt P27986) and the SH2-domain-containing adapter GRB2 (GRB2, UniProt P62993). GRB2 binds the guanine nucleotide exchange factor SOS (SOS1, UniProt Q07889), coupling IGF1R activation to Ras and the MAPK cascade. The IRS scaffold thus acts as the central branch point distributing signal to the two major downstream arms. (PMID 9393999)

IRS-1 and IRS-2 are themselves subject to negative feedback regulation: serine phosphorylation of IRS-1 at Ser307 (human) and multiple other serine residues by mTORC1/S6K1 and other kinases converts the adapter into an inhibitory molecule, decoupling it from the activated receptor. This serine-phosphorylation feedback is a key mechanism of insulin/IGF-1 resistance.

PI3K/AKT/mTOR Branch

Phosphorylated IRS-1/2 recruits class I PI3K through the SH2 domain of the p85 regulatory subunit. PI3K catalytic subunits (PIK3CA, PIK3CB, PIK3CD) phosphorylate the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 serves as a docking site for proteins carrying PH domains, including PDK1 (PDPK1, UniProt O15530) and AKT (protein kinase B, AKT1/2/3, UniProt P31749/P31751/Q9Y243).

PDK1 phosphorylates AKT at Thr308 in the kinase domain activation loop; mTOR complex 2 (mTORC2) phosphorylates AKT at Ser473 in the hydrophobic motif. Both phosphorylations are required for full AKT activation. The phosphatase PTEN (PTEN, UniProt P60484) opposes PI3K by dephosphorylating PIP3 back to PIP2, acting as the principal negative regulator of this arm.

Activated AKT phosphorylates a broad range of substrates:

• mTORC1 activation: AKT phosphorylates and inactivates TSC2 (TSC2, UniProt P49815), which otherwise maintains the mTOR activator Rheb in its GDP-bound (inactive) state. Disinhibited Rheb-GTP activates mTORC1 (MTOR, UniProt P42345), a serine/threonine kinase complex that promotes ribosome biogenesis and protein synthesis through phosphorylation of S6K1 (RPS6KB1) and the translational repressor 4E-BP1 (EIF4EBP1). (PMID 22226704)
• FOXO suppression: AKT phosphorylates FOXO1/3/4 transcription factors (FOXO1, FOXO3, FOXO4), excluding them from the nucleus and suppressing their pro-apoptotic and atrophy gene programs (including FBXO32/atrogin-1 and TRIM63/MuRF1 in muscle).
• GSK3 inhibition: AKT phosphorylates and inactivates GSK3alpha/beta (GSK3A/B), promoting glycogen synthesis and sparing beta-catenin from proteasomal degradation.
• BAD phosphorylation: AKT phosphorylates BAD (BAD, UniProt Q92934), preventing its interaction with anti-apoptotic BCL-2 family members and reducing the apoptotic signal.

MAPK/ERK Branch

In parallel, GRB2/SOS recruitment to phosphorylated IRS-1 activates RAS (predominantly KRAS, NRAS, UniProt P01116/P01111) by catalyzing GDP-to-GTP exchange. Active Ras-GTP recruits RAF kinase (RAF1, UniProt P04049) to the plasma membrane, which phosphorylates and activates MEK1/2 (MAP2K1/2, UniProt Q02750/P36507). MEK1/2 are dual-specificity kinases that phosphorylate and activate ERK1/2 (MAPK3/MAPK1, UniProt P27361/P28482) on Thr202/Tyr204 (ERK1) and Thr185/Tyr187 (ERK2).

Active ERK1/2 translocate to the nucleus and phosphorylate transcription factors including ELK1 (ELK1, UniProt P19419) and RSK (RPS6KA1/3), driving expression of immediate-early genes (FOS, JUN, MYC) and cyclins. In non-dividing differentiated cells such as skeletal myofibers, cytoplasmic ERK1/2 substrates including ribosomal S6 kinase (RSK) contribute to translational control and protein synthesis complementary to the mTORC1 arm.

JAK2-STAT5 Arm

Beyond the canonical RTK-IRS-PI3K/MAPK axis, IGF1R signals through a JAK2-STAT5 branch that parallels the canonical GH receptor pathway. This arm has been documented in multiple cell types including hepatocytes, mammary epithelium, immune cells, and hematopoietic progenitors.

JAK2 (JAK2, UniProt O60674) associates constitutively with the cytoplasmic tail of the GHR and is also recruited to and activated by activated IGF1R and the IR/IGF1R hybrid receptor. IGF-1-stimulated JAK2 phosphorylates STAT5A (STAT5A, UniProt P42229) and STAT5B (STAT5B, UniProt P51692) at their conserved tyrosine residues (Tyr694 on STAT5A, Tyr699 on STAT5B). Tyrosine-phosphorylated STAT5 forms homodimers or STAT5A/B heterodimers that translocate to the nucleus and bind gamma-activated sequence (GAS) elements in target gene promoters.

STAT5 target genes in the context of GH/IGF-1 signaling include:

• IGF1 itself (STAT5 drives hepatic IGF-1 transcription downstream of GHR/JAK2) (PMID 9393999)
• CISH and SOCS2/3 (cytokine-inducible SH2 proteins; negative feedback on JAK2)
• PRLR (prolactin receptor; cross-regulation)
• Mammary gland differentiation genes (CSN2/beta-casein, WAP)
• Hematopoietic survival genes (BCL2L1, MCL1)

STAT5B is the dominant isoform for GH-stimulated hepatic IGF1 transcription. Targeted deletion of STAT5B in mice produces a severe IGF-1 deficiency phenotype comparable to GH insensitivity, confirming this arm as essential for endocrine IGF-1 production. (PMID 9393999)

The SOCS proteins (particularly SOCS2 and SOCS3) induced by STAT5 act as negative feedback regulators: they bind JAK2 directly and also target signaling components for proteasomal ubiquitination via elongin-C/cullin E3 ligase complexes, terminating the JAK2-STAT5 signal.

Negative Regulatory Components

Signal Flow Diagram

flowchart TD
    subgraph Upstream["Upstream Inputs"]
        GH["Growth Hormone (GH1)<br/>Pituitary somatotrophs"]
        GHR_node["GHR (P10912)<br/>GH receptor<br/>Liver / periphery"]
        JAK2_liver["JAK2 (O60674)<br/>JAK2 on GHR"]
        STAT5_liver["STAT5B (P51692)<br/>Nuclear translocation"]
        IGF1_gene["IGF1 transcription<br/>Hepatocytes"]
        IGF1_circ["Circulating IGF-1 (P05019)<br/>+/- IGFBP-3 complex"]
    end

    subgraph Receptor["IGF1R at Target Tissues"]
        IGF1R["IGF1R (P08069)<br/>IGF1R gene, 15q26.3<br/>Heterotetrameric alpha-2/beta-2 RTK<br/>Tyr1158/1162/1163 autophosphorylation"]
    end

    subgraph Adapters["Adapter Layer"]
        IRS1["IRS-1/2 (P35568 / Q9Y4H2)<br/>Multi-site tyrosine phosphorylation<br/>Central branch point"]
        GRB2_SOS["GRB2 / SOS1<br/>Ras exchange factor recruitment"]
    end

    subgraph PI3K_arm["PI3K / AKT / mTOR Arm"]
        PI3K["PI3K (PIK3CA/PIK3R1)<br/>PIP2 -> PIP3"]
        PTEN_node["PTEN (P60484)<br/>Opposes PI3K"]
        PDK1["PDK1 (O15530)<br/>AKT Thr308 phosphorylation"]
        AKT["AKT1/2/3 (P31749)<br/>Ser473 (mTORC2) + Thr308 (PDK1)"]
        mTORC1_node["mTORC1 / MTOR (P42345)<br/>S6K1 + 4E-BP1 phosphorylation"]
        FOXO["FOXO1/3 suppression<br/>Atrophy gene inhibition"]
        BAD_node["BAD phosphorylation<br/>Anti-apoptotic"]
        GSK3_node["GSK3 inhibition<br/>Glycogen synthesis"]
    end

    subgraph MAPK_arm["MAPK / ERK Arm"]
        RAS_node["RAS (KRAS / NRAS)<br/>GDP -> GTP exchange"]
        RAF_node["RAF1 (P04049)"]
        MEK_node["MEK1/2 (MAP2K1/2)"]
        ERK_node["ERK1/2 (MAPK3/MAPK1)<br/>P27361 / P28482"]
        FOS_JUN["FOS / JUN / MYC<br/>Immediate-early transcription"]
    end

    subgraph JAK2_arm["JAK2-STAT5 Arm"]
        JAK2_rec["JAK2 (O60674)<br/>Recruited to IGF1R / GHR"]
        STAT5_rec["STAT5A/B (P42229 / P51692)<br/>Tyr694/699 phosphorylation"]
        GAS_elements["GAS element-driven transcription<br/>IGF1, SOCS2, CISH, BCL2L1"]
        SOCS_feedback["SOCS2/3 negative feedback<br/>JAK2 ubiquitination"]
    end

    subgraph Outputs["Physiological Outputs"]
        O1["Skeletal muscle hypertrophy<br/>mTORC1 / protein synthesis / FOXO suppression"]
        O2["Somatic growth<br/>Chondrocyte proliferation / linear bone growth"]
        O3["Adipose remodeling<br/>Lipolysis suppression (fed state); fat mass regulation"]
        O4["Glucose metabolism<br/>GLUT4 translocation; glycogen synthesis via GSK3"]
        O5["Cell survival / anti-apoptosis<br/>BAD, BCL-2 family; FOXO suppression"]
        O6["Hepatic IGF-1 output<br/>STAT5B-driven IGF1 gene expression"]
    end

    subgraph Compounds["Research Compounds"]
        IGF1LR3["IGF-1 LR3<br/>Direct IGF1R agonist<br/>Extended half-life"]
        Sermo["Sermorelin<br/>GHRH(1-29); GH pulse induction"]
        Tesa["Tesamorelin<br/>GHRH analog; FDA-approved"]
        CJC["CJC-1295<br/>Long-acting GHRH analog"]
    end

    GH --> GHR_node
    GHR_node --> JAK2_liver
    JAK2_liver --> STAT5_liver
    STAT5_liver --> IGF1_gene
    IGF1_gene --> IGF1_circ

    IGF1_circ -->|"IGF1R binding<br/>displaces IGFBP-3"| IGF1R
    IGF1R --> IRS1
    IRS1 --> GRB2_SOS
    IRS1 --> PI3K

    PI3K -->|"PIP2 -> PIP3"| PDK1
    PTEN_node -.->|"Opposes"| PI3K
    PDK1 --> AKT
    AKT --> mTORC1_node
    AKT --> FOXO
    AKT --> BAD_node
    AKT --> GSK3_node

    GRB2_SOS --> RAS_node
    RAS_node --> RAF_node
    RAF_node --> MEK_node
    MEK_node --> ERK_node
    ERK_node --> FOS_JUN

    IGF1R --> JAK2_rec
    JAK2_rec --> STAT5_rec
    STAT5_rec --> GAS_elements
    GAS_elements --> SOCS_feedback
    SOCS_feedback -.->|"Negative feedback"| JAK2_rec

    mTORC1_node --> O1
    FOXO --> O1
    ERK_node --> O2
    mTORC1_node --> O2
    AKT --> O3
    GSK3_node --> O4
    BAD_node --> O5
    GAS_elements --> O6

    IGF1LR3 -->|"Direct IGF1R agonist"| IGF1R
    Sermo -->|"GHRH receptor -> GH pulse -> GHR"| GHR_node
    Tesa -->|"GHRH receptor -> GH pulse -> GHR"| GHR_node
    CJC -->|"Long-acting GHRH -> GH -> GHR"| GHR_node

Physiological Outputs

Somatic Growth and Skeletal Development

Linear bone growth depends on IGF-1-driven proliferation and hypertrophy of chondrocytes in the epiphyseal growth plate. IGF1R expressed on proliferating and pre-hypertrophic chondrocytes couples to PI3K/AKT and MAPK/ERK cascades, promoting chondrocyte column expansion and matrix synthesis. mTORC1 within this cell population drives ribosome biogenesis and the anabolic gene program required for hypertrophic chondrocyte differentiation.

Studies in mice with chondrocyte-specific Igf1r deletion demonstrate severe growth retardation with short limbs and reduced body length, establishing IGF1R as non-redundant for growth plate function. (PMID 17245430) Circulating IGF-1 deficiency (from liver-specific Igf1 deletion) produces a milder growth phenotype, indicating that locally produced IGF-1 in bone is partially sufficient; the endocrine and paracrine pools are additive.

STAT5B’s role in hepatic IGF1 transcription makes this JAK2-STAT5 arm the primary driver of circulating IGF-1 concentrations. Inactivating human STAT5B mutations cause severe short stature, IGF-1 deficiency, and GH insensitivity that mirrors Laron syndrome clinically. (PMID 9393999)

Skeletal Muscle Mass and Protein Synthesis

In mature skeletal myofibers and satellite cells, IGF1R/IRS-1/PI3K/AKT/mTORC1 is the canonical hypertrophic pathway. AKT phosphorylates TSC2, disinhibiting mTORC1, which activates S6K1 and 4E-BP1 to increase cap-dependent mRNA translation and protein synthesis rate. The same AKT signal phosphorylates FOXO1 and FOXO3, sequestering them in the cytoplasm and blocking transcription of the E3 ubiquitin ligases atrogin-1 (FBXO32) and MuRF1 (TRIM63), which otherwise drive ubiquitin-proteasomal protein degradation and muscle atrophy. (PMID 22226704)

IGF-1 also stimulates muscle satellite cell activation and differentiation through ERK1/2-dependent upregulation of MYOD1 and MYOG, facilitating myonuclear accretion required for hypertrophy beyond the stretch of existing myofibers.

The negative feedback loop through mTORC1/S6K1 serine phosphorylation of IRS-1 limits the duration of the anabolic signal and is one mechanism by which chronically elevated IGF-1 or insulin signaling paradoxically produces insulin resistance despite continued mTORC1 activity.

Adipose Tissue Remodeling

In adipocytes, AKT promotes GLUT4 (SLC2A4) translocation to the plasma membrane and suppresses lipolysis by inhibiting hormonesensitive lipase (HSL, LIPE) through phosphodiesterase 3B (PDE3B)-mediated reduction of cAMP. The net effect in the postprandial state is fat storage (lipogenesis amplified by mTORC1-driven SREBP-1c activation) and reduced fatty acid release.

Tesamorelin’s primary clinical indication, HIV-associated lipodystrophy, reflects the GH axis regulation of visceral adipose tissue. GH pulses generated by GHRH receptor stimulation reduce visceral fat through direct GH effects on adipocyte lipolysis (via beta3-AR and cAMP/PKA/HSL), distinct from but complementary to IGF-1’s anti-lipolytic adipocyte actions. This apparent paradox reflects the cell-type-specific and temporal context-dependence of GH/IGF-1 signaling in fat depots. (PMID 20823776)

Glucose Homeostasis

IGF-1 suppresses hepatic glucose output and promotes peripheral glucose uptake, producing an insulin-like hypoglycemic effect. At physiological concentrations this is modest because IGF-1 circulates mostly IGFBP-3-bound; free IGF-1 concentrations are low. However, supraphysiological free IGF-1 concentrations (as may occur with high-dose IGF-1 LR3 research protocols) can produce hypoglycemia through both IGF1R and IR cross-activation.

Within the pancreatic islet, beta-cell IGF1R/IRS-2/PI3K/AKT signaling promotes beta-cell survival, proliferation, and glucose-stimulated insulin secretion; beta-cell-specific Igf1r deletion in rodents accelerates diabetes onset under metabolic stress. (PMID 25431053)

Cell Survival and Anti-Apoptosis

The PI3K/AKT/BAD axis is the principal survival signal downstream of IGF1R. AKT-mediated BAD phosphorylation at Ser136 prevents BAD from displacing BCL-XL (BCL2L1, UniProt Q07817) and BCL-2 (BCL2, UniProt P10415) from pro-apoptotic BAX, preserving mitochondrial membrane integrity. AKT also activates IKK, promoting NF-kappaB survival gene transcription, and directly phosphorylates the proapoptotic procaspase-9 at Ser196 to reduce its activation. This anti-apoptotic network is upregulated in many cancers through oncogenic IGF1R signaling, amplification of PIK3CA, or loss of PTEN.

Related Compounds

IGF-1 LR3

IGF-1 LR3 (Long R3 IGF-1) is a synthetic analog of human IGF-1 in which an arginine is substituted at position 3 and a 13-amino-acid extension is added to the N-terminus. These modifications reduce binding affinity for IGFBP-3 and other IGFBPs by approximately 1000-fold, converting the molecule to a predominantly free form that is bioavailable immediately upon administration. The result is a substantially extended effective half-life relative to unmodified IGF-1, estimated at 20-30 hours versus the minutes-to-hours bioactivity of free IGF-1.

IGF-1 LR3 activates IGF1R at the same orthosteric site as endogenous IGF-1 and engages the full signaling network described above: IRS-1/2 phosphorylation, PI3K/AKT/mTORC1 activation, MAPK/ERK activation, and JAK2-STAT5 engagement. Because it bypasses IGFBP regulation, it represents the most direct pharmacological tool for studying IGF1R-dependent biology in isolation from the GH-JAK2-STAT5 hepatic axis.

Research hub: IGF-1 LR3 Research

Sermorelin

Sermorelin (also designated GRF 1-29 NH2) corresponds to the first 29 amino acids of human growth hormone-releasing hormone (GHRH), which constitute the pharmacophore responsible for GHRH receptor (GHRHR, GHRHR, UniProt P32082) activation. GHRHR is a Class B GPCR expressed on pituitary somatotrophs that couples to Gs, activating adenylyl cyclase, elevating cAMP, and activating PKA/CREB signaling to drive GH1 transcription and GH secretory granule release.

Sermorelin stimulates pulsatile GH release from somatotrophs. The resulting GH pulses reach the liver, bind GHR, and activate JAK2-STAT5, driving the hepatic IGF1 transcription that raises circulating IGF-1. Sermorelin thus engages the IGF-1/JAK2-STAT5 axis at its most upstream regulated step. Its pulsatile mechanism of action preserves physiological somatotroph feedback sensitivity, making it distinct from continuous rhGH administration. The FDA approved sermorelin acetate (as Geref) for GH deficiency evaluation and pediatric growth disorders. (PMID 17245430)

Research hub: Sermorelin Research

Tesamorelin

Tesamorelin is a synthetic analog of GHRH incorporating a trans-3-hexenoic acid moiety conjugated to the tyrosine at position 1. This modification confers resistance to dipeptidyl peptidase IV (DPP-IV)-mediated N-terminal cleavage, the primary route of GHRH inactivation in plasma, extending the half-life approximately fourfold relative to native GHRH. Like sermorelin, tesamorelin activates GHRHR/Gs in somatotrophs, drives GH pulses, and consequently elevates circulating IGF-1 via the hepatic GHR/JAK2-STAT5 axis.

Tesamorelin received FDA approval (NDA 022505) in November 2010 for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. Phase III trials (NCT00597454, NCT00705900) demonstrated significant reductions in trunk fat measured by DEXA and CT at 26 weeks versus placebo, with IGF-1 increases confirming on-target GH axis engagement. (PMID 20823776) The approved indication is mechanistically supported by GH’s direct lipolytic action on visceral adipocytes operating in parallel with IGF-1 pathway effects.

Research hub: Tesamorelin Research

CJC-1295

CJC-1295 is a GHRH analog incorporating four amino acid substitutions relative to native GHRH(1-29) to improve metabolic stability, plus a maleimide-containing Drug Affinity Complex (DAC) linker at the C-terminus. The DAC moiety reacts with free cysteine-34 on circulating albumin after subcutaneous administration, creating a covalent albumin-peptide complex that markedly extends the effective half-life to several days. This converts the compound from a short-acting pulsatile GH secretagogue to a sustained GHRHR agonist producing near-continuous GH elevation.

At the receptor level, CJC-1295 engages GHRHR/Gs in the same manner as sermorelin and tesamorelin, raising cAMP and GH output. Sustained GHRHR stimulation, however, produces a more continuous rather than pulsatile pattern of GH and IGF-1 elevation, which may affect receptor sensitization kinetics relative to pulsatile secretagogues. Clinical pharmacokinetic studies documented mean IGF-1 increases of 1.5- to 3-fold above baseline with weekly CJC-1295 administration that persisted for 14-21 days post-dose. (PMID 16352683)

Because CJC-1295 acts upstream of IGF1R (through GHRHR, then GHR, then JAK2-STAT5, then hepatic IGF1 transcription), its effects on the signaling cascade described in this page are entirely indirect, mediated through endogenous IGF-1 elevation.

Research hub: CJC-1295 Research

Key Molecular Targets Summary

Primary Literature

Pathway Context

The IGF-1/JAK2-STAT5 axis sits downstream of the Growth Hormone Receptor pathway (/pathways/growth-hormone-receptor/), which is the primary driver of hepatic IGF-1 production. The PI3K/AKT/mTOR signaling arm described here is elaborated further in the PI3K-Akt Pathway (/pathways/pi3k-akt-pathway/) and the mTOR Signaling (/pathways/mtor-signaling/) pages, which cover these cascades in additional biological contexts. The RAS-RAF-MEK-ERK arm connects to the MAPK Cascade (/pathways/mapk-cascade/), through which IGF-1 drives cell proliferation, differentiation, and gene expression programs in both normal physiology and oncogenic signaling.

See also

Compounds that engage this pathway:

• IGF-1 LR3
• Sermorelin
• Tesamorelin
• CJC-1295