Cell Signaling
Signals pass through branching networks, with outcomes shaped by cell type and context.
See how the pieces connect
- Step 1EGF signala growth-factor example outside the cell
- Step 2EGFRa receptor input that can branch into both networks
- Step 3RAS-GTPKRAS is one human RAS isoform and an example node
- Step 4RAF-MEK-ERKthe core MAPK kinase relay
- Step 5ERK responseERK2 acts on targets; outcomes depend on context
An EGFR signal can feed more than one route. Through adaptor proteins, it can promote RAS-GTP and the RAF-MEK-ERK relay. Receptor-associated signals and RAS can also engage PI3K, leading to PIP3 and regulated AKT signaling. The balance depends on the cell, its state, and feedback; this map is a selected teaching model, not a universal response.
Read the supporting reference: Reactome · Signaling by EGFR (R-HSA-177929)EGFR can feed two connected growth-signaling networks
Compare the RAS-RAF-MEK-ERK relay with the PI3K-AKT-mTORC1 network, then inspect where they share inputs.
MAPK: receptor to RAS
A representative growth-factor input activates the RAS switch
- EGFOutside the cellA growth-factor ligand used here as one example input.Open record ↗
- binds and activatesEGFRPlasma membraneA receptor tyrosine kinase that can signal into more than one intracellular network.Open record ↗
- can recruitGRB2Inner membrane surfaceAn adaptor that helps connect activated receptors to RAS-activating machinery.Open record ↗
- recruitsSOS1Receptor-associated complexA nucleotide-exchange factor that helps switch RAS from GDP-bound to GTP-bound.Open record ↗
- promotes GDP-to-GTP exchange onRAS-GTP (KRAS example)Inner membrane surfaceActive KRAS is one example of the RAS family; RAS proteins have multiple effectors.Open record ↗
MAPK: kinase relay
The core RAF-MEK-ERK module; RAF dimers and feedback tune activity
- RAS-GTPPlasma membrane and other sitesThe GTP-bound switch can recruit RAF proteins.Open record ↗
- recruits and supports activation ofRAF kinasesMembrane-associated signaling complexBRAF and RAF1 are examples; RAF proteins can form dimers.Open record ↗
- phosphorylatesMEK1 / MEK2CytoplasmMAP2K1 and MAP2K2 carry the signal to ERK proteins.Open record ↗
- phosphorylatesERK1 / ERK2Cytoplasm and nucleusMAPK3 and MAPK1 act on cytoplasmic and nuclear targets; responses depend on context.Open record ↗
PI3K: membrane signal to AKT
A lipid signal brings kinases together at the membrane
- EGFRPlasma membraneOne receptor input; adaptor proteins help recruit signaling partners.Open record ↗
- can recruit adaptors that engageClass IA PI3KInner membrane surfaceA p85-p110 lipid-kinase complex; PIK3CA encodes one common catalytic subunit.Open record ↗
- converts PIP2 intoPIP3Plasma membraneA membrane lipid signal made from PIP2 and opposed by PTEN.Open record ↗
- helps recruit and localizeAKT (AKT1 example)Membrane and cytoplasmPIP3 helps recruit AKT and PDPK1. PDPK1 can phosphorylate AKT at T308; mTORC2 can phosphorylate S473.Open record ↗
AKT to mTORC1 outputs
Growth factors are only one input; mTORC1 also senses nutrients and energy
- AKTCytoplasmAKT1 is shown; AKT has multiple isoforms and substrates.Open record ↗
- can inhibitTSC1-TSC2 complexCytoplasm and lysosomeThis regulatory complex restrains RHEB and can reduce mTORC1 activation.Open record ↗
- normally restrainsRHEB-GTPLysosomal surfaceThe GTP-bound state can activate mTORC1.Open record ↗
- can activatemTORC1Cytoplasm and lysosomeA multi-protein complex distinct from mTORC2; its activity depends on several signals.Open record ↗
- phosphorylates targets includingS6K1 / 4E-BP1CytoplasmmTORC1 regulates translation through substrates including these proteins.Open record ↗
Where the routes meet
Shared inputs do not make the networks identical or interchangeable
HER2-containing receptor context
HER2 has no established soluble ligand of its own; it can pair with ligand-activated ERBB receptors
- EGFR–HER2 heterodimerPlasma membraneA representative receptor pair. Ligand-bound EGFR can pair with HER2 and activate downstream networks.Open record ↗
- can signal throughERBB / receptor tyrosine kinase signalingIntracellular networkAn ERBB2-containing complex can feed MAPK and PI3K–AKT signaling; which branch dominates depends on context.Open record ↗
Selected human-cell teaching map, not a complete signaling model. EGFR and other receptors can feed different branches; GTP-bound RAS can engage RAF and PI3K. AKT and mTORC1 outputs vary with isoforms, cell state, feedback, and subcellular location. mTORC1 also integrates amino-acid, energy, and oxygen signals, so neither pathway is a deterministic chain to one cell fate.
A GPCR signal becomes a cAMP message
Follow one Gs-coupled route, then compare three separate controls that shorten, remove, or redirect the signal.
Activate a Gs-coupled receptor
The receptor catalyzes GDP release and GTP binding on its partner G protein
- GPCR agonistOutside the cellA ligand example: different receptors and agonists can engage different G-protein families.Open record ↗
- activatesGs-coupled GPCRPlasma membraneAn activated receptor can promote nucleotide exchange on an associated heterotrimeric G protein.Open record ↗
- promotes GDP-to-GTP exchange onGαs: GDP → GTPInner membrane surfaceThe active GTP-bound state can stimulate adenylyl cyclases; the GNAS locus has multiple gene products.Open record ↗
Make and read the second messenger
ADCY5 is one adenylyl cyclase isoform; cAMP has effectors beyond PKA
- Gαs-GTPInner membrane surfaceA stimulatory G-protein state that can regulate several adenylyl cyclase isoforms.Open record ↗
- stimulatesAdenylyl cyclase (ADCY5 example)Plasma membraneA membrane enzyme that converts ATP to cyclic AMP; ADCY5 is one of multiple isoforms.Open record ↗
- synthesizes from ATPcAMPCytoplasmA local second messenger that can regulate PKA and other effectors.Open record ↗
- can activatePKA holoenzymeCytoplasmcAMP binds regulatory subunits and releases catalytic subunits such as PRKACA.Open record ↗
- phosphorylates targets includingTarget phosphorylationCytoplasm and nucleusPKA can phosphorylate targets such as CREB; cell state and substrate access shape the response.Open record ↗
Signal termination and receptor control
These mechanisms act at different points and are not interchangeable
- Distinct controlRGS proteinsG-protein switchSome RGS proteins act as GAPs for selected Gα families and accelerate GTP-to-GDP hydrolysis.Open record ↗
- Distinct controlPDE4DSecond-messenger turnoverA cAMP-selective phosphodiesterase example that hydrolyzes cAMP to AMP.Open record ↗
- Distinct controlβ-arrestinReceptor traffickingCan uncouple phosphorylated receptors from G proteins and promote internalization; arrestins can also scaffold signaling.Open record ↗
This is one representative GPCR branch. Ligand-bound receptors promote nucleotide exchange; Gαs does not exchange GDP for GTP by itself. RGS/GAP activity is Gα-family-specific, phosphodiesterases convert cAMP to AMP, and β-arrestins can both uncouple receptors and scaffold other signals.
An insulin signal moves GLUT4
One well-studied route links a hormone at the cell surface to glucose transport in muscle and fat cells.
From the outside in
A receptor turns an extracellular message into intracellular signals
- InsulinExtracellularA hormone signal that rises after food intake.Open record ↗
- binds and activatesInsulin receptorPlasma membraneA receptor tyrosine kinase; ligand binding triggers autophosphorylation.Open record ↗
- phosphorylates docking proteins that recruitIRS proteins + PI3KInner membrane surfaceAdaptor proteins recruit PI3K, a lipid kinase.Open record ↗
- converts membrane PIP₂ toPIP₃Plasma membraneA signaling lipid that helps recruit proteins with PH domains.Open record ↗
- which recruits kinases that activatePDK1 + AKTCytosol / membranePIP₃ helps bring signaling proteins together; AKT activation is regulated by multiple kinases.Open record ↗
Glucose transport response
A trafficking signal changes how much GLUT4 is at the cell surface
- AKTCytosolOne important branch phosphorylates TBC1D4/AS160.Open record ↗
- phosphorylates targets includingTBC1D4 / AS160CytosolA Rab GTPase-activating protein involved in vesicle trafficking.
- which regulates Rab proteins and movement ofGLUT4 vesiclesInside muscle / fat cellStorage vesicles move, dock, and fuse with the cell membrane.Open record ↗
- to the surface, where it transportsGlucose uptakeAcross plasma membraneGLUT4 enables facilitated glucose transport down its concentration gradient.Open record ↗
This is a representative pathway, not a universal insulin response. GLUT4 is prominent in skeletal muscle and adipose tissue; exercise and other signals also affect its trafficking. Insulin signaling branches and differs by tissue and context.
Which statement best describes how active RAS connects the two signaling networks?
Topics in this branch
Cell Signaling
How cells detect information and convert it into changes in behavior, chemistry, or gene activity.
Explore this idea 02Ligands And receptors
A ligand is a molecule that binds a specific partner, such as a receptor, and can change its activity.
Explore this idea 03Insulin
A hormone that helps coordinate nutrient use and storage after food intake.
Explore this idea 04Insulin Receptor
A cell-surface receptor that detects insulin and initiates intracellular signaling.
Explore this idea 05Insulin Signaling
How insulin receptor signaling coordinates glucose uptake and nutrient storage.
Explore this idea 06GLUT4 Glucose uptake
Insulin and muscle contraction can move GLUT4 transporters to the surface of muscle and adipose cells.
Explore this idea 07GPCR Signaling
How G-protein-coupled receptors convert outside signals into intracellular changes.
Explore this idea 08Receptor Tyrosine kinase signaling
How growth-factor receptors use phosphorylation to assemble signaling networks.
Explore this idea 09Second Messengers
Small intracellular signals that relay and distribute information after many receptors are activated.
Explore this idea 10Signal Amplification
A signaling process in which one activated component influences many downstream molecules.
Explore this idea 11Protein Kinases
Enzymes that transfer phosphate groups, usually from ATP, onto protein targets.
Explore this idea 12Protein Phosphatases
Enzymes that remove phosphate groups from proteins and help balance kinase activity.
Explore this idea 13Protein Phosphorylation
A reversible chemical modification that can change a protein's activity or interactions.
Explore this idea 14Feedback In signaling
Signals can feed back to strengthen, weaken, or reshape the pathway that produced them.
Explore this idea 15RAS-RAF-MEK-ERK Signaling (MAPK)
A growth-signal network whose core RAS-RAF-MEK-ERK relay regulates cell responses, with output shaped by feedback, location, and cell context.
Explore this idea 16PI3K-AKT-mTOR Signaling
A growth- and nutrient-responsive network in which PI3K lipid signals regulate AKT and connect with mTORC1, metabolism, survival, and biosynthesis.
Explore this idea 17JAK–STAT Signaling
A direct route from selected cytokine receptors to transcriptional responses.
Explore this idea 18Wnt Signaling
A family of signals with important roles in development, tissue renewal, and cell fate.
Explore this idea 19TGF-β Signaling
A receptor-kinase network that regulates development, immune responses, and tissue remodeling.
Explore this idea 20Apoptosis Signaling
The regulated pathways cells use to initiate and execute programmed cell death.
Explore this idea 21Gs–cAMP–PKA Signaling
A common GPCR branch in which Gαs stimulates cyclic AMP production and cAMP regulates protein kinase A and other effectors.
Explore this idea 22RGS Proteins
Regulators of G-protein signaling that accelerate GTP hydrolysis by selected heterotrimeric Gα subunits.
Explore this ideaReceptors and the RAS–MAPK Route
EGF
A growth-factor ligand produced by processing a larger precursor. EGF can bind EGFR and trigger receptor signaling.
Open record ProteinEGFR
EGFR is a receptor tyrosine kinase. Ligand binding can promote receptor pairing and phosphorylation, creating docking sites for adaptors that connect to RAS–RAF–MEK–ERK and PI3K–AKT signaling. Which branches dominate depends on receptor abundance, trafficking, ligand, and cell state.
Open record ProteinHER2 (ERBB2)
A member of the ERBB receptor family. HER2 has no established soluble ligand of its own and can participate in signaling as a partner for other ERBB receptors.
Open record ProteinHER3 (ERBB3)
An ERBB-family receptor with weak intrinsic kinase activity. HER3 can signal by pairing with kinase-active ERBB partners, including HER2.
Open record ProteinSHC1
An adaptor protein that can help assemble signaling complexes downstream of activated cell-surface receptors.
Open record ProteinGRB2
An adaptor protein that helps recruit SOS-family exchange factors to activated receptor signaling complexes.
Open record ProteinSOS1
A RAS guanine-nucleotide exchange factor. When recruited to signaling complexes, SOS1 can promote the active, GTP-bound state of RAS.
Open record ProteinKRAS
A molecular switch that cycles between GDP-bound and GTP-bound states. Active KRAS can recruit RAF and engage other effectors, including PI3K.
Open record ProteinBRAF
A RAF-family kinase that relays signals from RAS toward MEK1 and MEK2. Its activity depends on cellular context and regulatory interactions.
Open record ProteinRAF1 (C-RAF)
A RAF-family kinase that can relay RAS signals to MEK. RAF proteins can form dimers, so the pathway is more context-dependent than a single straight chain.
Open record ProteinMEK1 (MAP2K1)
A dual-specificity kinase in the MAPK cascade. MEK1 phosphorylates ERK proteins downstream of RAF-family kinases.
Open record ProteinMEK2 (MAP2K2)
A dual-specificity kinase in the MAPK cascade. MEK2 phosphorylates ERK proteins downstream of RAF-family kinases.
Open record ProteinERK1 (MAPK3)
A MAP kinase activated by MEK1 or MEK2. ERK1 can phosphorylate many targets; its effects depend on the cell and signal context.
Open record ProteinERK2 (MAPK1)
A MAP kinase activated by MEK1 or MEK2. ERK2 can phosphorylate many targets and move into the nucleus after some signals.
Open record ProteinNeurofibromin (NF1)
A RAS GTPase-activating protein that promotes GTP hydrolysis and can reduce RAS pathway signaling.
Open record ProteinDUSP6
A dual-specificity phosphatase that can remove activating phosphates from ERK and contribute to feedback regulation.
Open record Multi-protein complexEGFR–HER2 Heterodimer
A representative ERBB receptor pair. Ligand-bound EGFR can pair with HER2; HER2 has no established soluble ligand of its own and can feed both MAPK and PI3K signaling through receptor-associated complexes.
Open recordThe PI3K–AKT–mTOR Route
Class IA PI3K
A regulatory p85 subunit and catalytic p110 subunit form a lipid kinase complex. When activated, it can convert PIP2 to PIP3, helping recruit AKT and other signaling proteins to the membrane.
Open record Proteinp110α (PIK3CA)
The catalytic subunit of a common class IA PI3K complex. Together with a regulatory subunit, it can phosphorylate PIP2 to form PIP3.
Open record Proteinp85α (PIK3R1)
A regulatory subunit of class IA PI3K. Receptor-associated signals can recruit the complex and change regulation of its catalytic subunit.
Open record MoleculePIP3
A membrane phospholipid signal made by PI3K from PIP2. PIP3 helps recruit AKT and other proteins to the cell membrane.
Open record ProteinPDK1 (PDPK1)
A kinase recruited in phosphoinositide signaling that phosphorylates AKT at threonine 308. This is distinct from pyruvate dehydrogenase kinases, which are also abbreviated PDKs.
Open record ProteinAKT1
A serine/threonine kinase recruited to the membrane by PIP3. AKT1 is phosphorylated by more than one kinase and regulates many targets involved in growth, survival, and metabolism.
Open record ProteinAKT2
An AKT kinase isoform recruited into phosphoinositide signaling. AKT2 has a prominent role in insulin-stimulated glucose transport in muscle and adipose tissue, while AKT isoform contributions overlap and depend on cellular context.
Open record ProteinTBC1D4 (AS160)
A Rab GTPase-activating protein that regulates GLUT4 vesicle traffic. Insulin-linked AKT phosphorylation of TBC1D4 is an important part of GLUT4 regulation in muscle and adipose cells; other signals and trafficking steps also contribute.
Open record ProteinGSK3β
A serine/threonine kinase that can inhibit glycogen synthase through phosphorylation. In insulin signaling, AKT-dependent inhibitory phosphorylation of GSK3B can help favor glycogen synthesis; multiple enzymes and signals regulate glycogen flux.
Open record ProteinFOXO1
A transcription factor whose activity and localization can be regulated by AKT-dependent phosphorylation. In hepatocytes, insulin-linked FOXO1 regulation can change expression of genes involved in glucose production; this is one part of broader liver control.
Open record ProteinPTEN
A lipid phosphatase that removes a phosphate from PIP3, opposing PI3K and reducing a signal that helps recruit AKT to the membrane.
Open record ProteinTSC1 (hamartin)
A component of the TSC1–TSC2 protein complex, which acts upstream of RHEB and helps regulate mTORC1.
Open record ProteinTSC2 (tuberin)
A catalytic component of the TSC1–TSC2 complex that promotes conversion of active RHEB-GTP toward RHEB-GDP, reducing mTORC1 activation.
Open record Multi-protein complexTSC1–TSC2 Complex
TSC1 and TSC2 form a regulatory complex that acts as a GTPase-activating protein for RHEB. This helps restrain RHEB-driven mTORC1 activity.
Open record ProteinRHEB
A small GTPase that can activate mTORC1 when GTP-bound. The TSC complex regulates the balance between RHEB nucleotide states.
Open record ProteinmTOR (MTOR)
A protein kinase that forms distinct complexes, including mTORC1 and mTORC2. Those complexes have different subunits and functions.
Open record ProteinRaptor (RPTOR)
A defining mTORC1 subunit that helps recruit substrates to the complex.
Open record ProteinmLST8 (MLST8)
A protein subunit found in both mTORC1 and mTORC2.
Open record ProteinRICTOR
A defining scaffold subunit of mTORC2. The mTORC2 complex can phosphorylate AKT at serine 473.
Open record Multi-protein complexmTORC1
A nutrient- and growth-responsive protein complex that coordinates cell growth with protein synthesis, nutrient use, and autophagy. It contains MTOR, RPTOR, and other subunits; it is not a single protein.
Open record Multi-protein complexmTORC2
A distinct MTOR-containing complex with RICTOR and other subunits. Among its roles, mTORC2 can phosphorylate AKT at serine 473; it differs in composition and regulation from mTORC1.
Open record ProteinS6K1 (RPS6KB1)
A kinase that can be activated downstream of mTORC1 and phosphorylate targets involved in protein synthesis and cell growth.
Open record Protein4E-BP1 (EIF4EBP1)
A translation-regulating protein. mTORC1-dependent phosphorylation can reduce 4E-BP1 binding to eIF4E, helping control translation initiation.
Open recordGPCR and cAMP Signaling
Gs–cAMP–PKA Signaling
A common GPCR branch in which Gαs stimulates cyclic AMP production and cAMP regulates protein kinase A and other effectors.
Open record ProteinGαs (GNAS)
The stimulatory alpha subunit of a heterotrimeric G protein. In its GTP-bound state, Gαs can stimulate adenylyl cyclase; GNAS has multiple gene products, so this record focuses on the Gαs signaling role.
Open record ProteinAdenylyl Cyclase 5 (ADCY5)
A membrane enzyme isoform that converts ATP to cyclic AMP. ADCY5 is one example of the adenylyl cyclases regulated by G-protein and other cellular inputs.
Open record MoleculeCyclic AMP
A small intracellular second messenger made by adenylyl cyclases downstream of selected receptors.
Open record Multi-protein complexProtein Kinase A (PKA)
A cAMP-regulated protein kinase assembled from regulatory and catalytic subunits. cAMP binding to the regulatory subunits can release active catalytic subunits; subunit composition and signaling are context-dependent.
Open record ProteinPKA Catalytic subunit alpha (PRKACA)
A catalytic subunit of protein kinase A. cAMP binding to regulatory subunits of the PKA holoenzyme releases active catalytic subunits; PRKACA is one catalytic isoform.
Open record ProteinPDE4D
A cAMP-selective phosphodiesterase isoform that hydrolyzes cyclic AMP to AMP. PDE4D splice variants and localization help shape local signal dynamics.
Open record ProteinRGS Proteins
Regulators of G-protein signaling that accelerate GTP hydrolysis by selected heterotrimeric Gα subunits.
Open record Proteinβ-arrestin
Adaptor proteins that can reduce GPCR coupling to G proteins and organize receptor trafficking or other signaling events.
Open record