A scientific community for researchers, students, and professionals interested in autocrine signaling, growth factor biology, receptor tyrosine kinases, and cell communication mechanisms. Share research insights and discuss the latest findings.
Posted by CellBioStudent · 34 replies
Autocrine signaling occurs when a cell secretes a signaling molecule that binds to receptors on the same cell, creating a self-stimulatory loop. Paracrine signaling involves short-range communication where secreted factors diffuse to affect nearby but distinct cell types. The distinction matters physiologically: autocrine loops are critical in development, immune responses (activated T-cells secrete IL-2 which drives their own proliferation), and cancer (tumor cells often establish autocrine loops with growth factors like EGF or VEGF that bypass normal growth regulation). Many physiological processes use both — during wound healing, platelets release PDGF acting paracrinely on fibroblasts while activated fibroblasts establish autocrine TGF-beta loops.
Posted by RTKResearcher · 47 replies
When an autocrine ligand like EGF binds its RTK (EGFR), it induces receptor dimerization — two receptor monomers come together, and their intracellular kinase domains transphosphorylate each other on specific tyrosine residues. These phosphotyrosine motifs serve as docking sites for SH2 domain-containing adaptor proteins that initiate downstream signaling cascades including Ras/MAPK, PI3K/Akt, and PLC-gamma/PKC pathways. The duration and intensity of RTK signaling is tightly regulated by receptor endocytosis — activated receptors are ubiquitinated by c-Cbl and internalized for recycling or lysosomal degradation. Mutations that prevent receptor degradation, like the EGFR truncation in some glioblastomas, amplify autocrine signaling pathways.
Posted by OncologyResearch · 56 replies
Autocrine growth factor loops are one of the hallmarks of cancer described by Hanahan and Weinberg. Cancer cells frequently acquire the ability to secrete growth factors (EGF, IGF, PDGF, HGF) that bind their own receptors, creating self-sufficient growth signals that bypass the normal requirement for exogenous mitogenic stimulation. This is achieved through increased ligand secretion, upregulated receptor expression, receptor mutations causing constitutive activation (like EGFR L858R in non-small cell lung cancer), or loss of negative regulators. Therapeutically targeting these loops with monoclonal antibodies (trastuzumab, cetuximab) or small molecule kinase inhibitors (erlotinib, gefitinib) has proven effective in tumors dependent on specific autocrine pathways.
Posted by ExperimentDesign · 28 replies
Classical approaches include conditioned medium experiments — collecting culture medium from cells and applying it to fresh cells of the same type to test for secreted stimulatory factors. To distinguish autocrine from paracrine, researchers use cell-conditioned medium on the original cell type versus a different cell type. Neutralizing antibodies against candidate ligands or receptor-blocking antibodies can confirm specific pathway involvement. Single-cell RNA sequencing has revolutionized autocrine loop discovery by enabling simultaneous profiling of ligand and receptor expression within the same cell, with computational tools like CellChat and NicheNet inferring active autocrine interactions from transcriptomic data.
Posted by GrowthFactorList · 39 replies
Epidermal Growth Factor (EGF) and its family members (TGF-alpha, amphiregulin, epiregulin, HB-EGF) are the most studied autocrine ligands, signaling through the EGFR/ErbB family. Transforming Growth Factor-beta (TGF-beta) operates in autocrine loops particularly in cancer-associated fibroblasts and during epithelial-to-mesenchymal transition. Insulin-like Growth Factors (IGF-1 and IGF-2) form autocrine loops in many cancers and are regulated by a complex system of binding proteins. Platelet-Derived Growth Factor (PDGF) isoforms act autocrinely in gliomas and mesothelioma. Interleukin-2 (IL-2) is the classic immune autocrine ligand, driving activated T-cell clonal expansion.
Posted by FeedbackMechanisms · 33 replies
Autocrine signaling is regulated at multiple levels to prevent runaway positive feedback. Ligand shedding by ADAM (A Disintegrin and Metalloproteinase) family proteases is rate-limiting for many EGF family autocrine ligands — ADAM10 and ADAM17 cleave membrane-anchored pro-ligands with tightly regulated activity. At the receptor level, activated EGFR is rapidly internalized and degraded, reducing surface receptor availability. Intracellularly, negative regulators like MIG-6/RALT bind activated EGFR and accelerate endocytosis, while protein tyrosine phosphatases dephosphorylate activated receptors. Transcriptional feedback also operates — EGF-stimulated cells upregulate ERRFI1 (MIG-6 gene), creating a delayed negative feedback that attenuates sustained signaling.
Posted by JuxtacrineVsAutocrine · 22 replies
Juxtacrine signaling requires direct cell-cell contact — a membrane-anchored ligand on one cell binds a receptor on an adjacent cell without a freely diffusible intermediate. Classic juxtacrine systems include Notch-Delta/Jagged signaling (critical in developmental boundary formation and stem cell niche maintenance) and Ephrin-Eph receptor signaling (involved in axon guidance and tissue compartmentalization). Some ligands like EGF family members and membrane-bound TNF can act in both modes — uncleaved membrane-anchored forms mediate juxtacrine signaling while shed soluble ectodomains mediate autocrine or paracrine signaling, allowing cells to integrate both contact-dependent and diffusible signals from their microenvironment.
Posted by DrugResistance · 51 replies
Autocrine loops contribute to therapeutic resistance through multiple mechanisms. When a targeted therapy blocks one pathway (e.g., erlotinib blocking EGFR), tumor cells can upregulate autocrine loops through alternative receptors — increased HGF secretion activating c-Met is a documented resistance mechanism to EGFR inhibitors in lung cancer. Autocrine IGF-1R and HER3 signaling frequently compensate for suppressed EGFR/HER2 signaling. Additionally, acquired mutations can amplify autocrine ligand secretion or constitutively activate downstream signaling nodes, rendering upstream autocrine loop inhibition ineffective. Combination therapies that simultaneously target multiple autocrine receptors are designed to address these resistance mechanisms.
Posted by Bioinformatics · 29 replies
CellChat (R package) constructs intercellular communication networks from single-cell RNA-seq data using a curated ligand-receptor database and explicitly models autocrine interactions within the same cell population. NicheNet prioritizes ligands based on their ability to explain observed target gene expression changes, integrating signaling and transcriptional network prior knowledge. COMMOT uses optimal transport theory to model ligand diffusion and predict communication distance, helping separate autocrine from paracrine contributions. CellPhoneDB focuses on heteromeric receptor complexes often missed by simpler pair-matching approaches. The FANTOM5 database's coexpression data for ligand-receptor pairs is useful for validating computationally predicted autocrine loops.
Posted by IntracellularAutocrine · 17 replies
Yes — intracrine signaling describes the situation where a ligand binds its receptor intracellularly, either in the endoplasmic reticulum, Golgi apparatus, or endosomal compartments, without being secreted extracellularly. This has been documented for several nuclear receptors and some growth factor systems. For EGFR, there's evidence of autocrine loop activation in the endoplasmic reticulum where newly synthesized receptor encounters ligand before trafficking to the cell surface. PTHrP (Parathyroid Hormone-related Protein) has a nuclear targeting sequence and can act intracellularly. The distinction between classical autocrine signaling and intracrine signaling has therapeutic implications, as secretion-blocking strategies would not block intracrine pathways.
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