Cell Signaling Pathways and Receptor Types in Biology

Cell junctions

Direct cytoplasmic exchange with channels

Gap junctions

Channels with chemical/electrical coupling

Tight junctions

Seals epithelial layers

Desmosomes

Anchors cells for tissue integrity

Adhesion contact

Direct physical contact between cells through membrane bound ligand receptor contact

Autocrine

Secretes signaling molecules that bind to its own receptors stimulating itself

Paracrine

Nearby cell signaling

Endocrine

Hormone through blood stream

Kinase

An enzyme that transfers phosphate groups to substrates altering activity.

Akt

A protein kinase (an enzyme that adds a P group to other proteins) ATP→ ADP.

MAPK

A signaling pathway involved in cell proliferation and survival.

Src

A non-receptor tyrosine kinase that phosphorylates tyrosine residues on various substrates to regulate cell adhesion, proliferation, and survival.

miRNA

Small non-coding RNA molecules that regulate gene expression.

Ligand-independent firing

Activation of a receptor without the binding of its normal ligand often due to mutations.

Growth factors

Substances (proteins) naturally produced in the body that regulate cell signaling pathways involved in proliferation and survival.

Epidermal GF

Activates EGFR → Ras/MAPK and PI3K/Akt pathways → proliferation.

HER2/neu (ErbB2)

Often amplified in 25% of breast cancers → constitutive receptor dimerization and signaling.

TGF-B

Has dual roles - tumor suppressor in early stages but promotes invasion and metastasis later.

Vascular endothelial GF

Promotes angiogenesis for tumor growth and metastasis.

Insulin-like GF

Promotes cell survival and growth via PI3K/Akt.

Paracrine GF

GF released by adjacent cell and signal transduction takes place in target cell.

Autocrine GF

Growth factor released by cell undergoing signal transduction.

Pleiotropic action of kinases

One molecule (kinase) affects many cellular functions at once.

GSK-3B

Blocks growth; inactivated by Akt phosphorylation leading to more cell proliferation.

HIG-1a

Responds to low O2; activated by Akt leading to more angiogenesis.

Bad

Promotes apoptosis; inactivated by Akt leading to cell survival.

TSC2

Inhibits growth and protein synthesis; inactivated by Akt leading to more protein production.

Receptor Tyrosine Kinase (RTK)

Transmembrane proteins with a tyrosine kinase domain that are activated by ligand binding.

Cytokine receptor

No intrinsic kinase; however associated with JAK kinases.

TGF-B receptors

Serine/Threonine kinase receptors that regulate transcription.

Frizzled

7 transmembrane GPCR-like receptors that bind Wnt ligands.

GCPR

7 transmembrane helices that activate adenylyl cyclase and generate cAMP as second messengers.

Integrin

Heterodimers (a and B subunits) that bind ECM proteins and trigger MAPK and PI3K/Akt signaling.

Cytokine Receptors

Do not have intrinsic kinase domains. Their cytoplasmic tails are non-covalently associated with JAK kinases (Janus kinases). Usually exist as monomers that dimerize upon ligand binding.

Activation of Cytokine Receptors

A cytokine (like interleukin-6, erythropoietin, or interferon) binds to the receptor. This causes receptor dimerization. The attached JAK kinases cross-phosphorylate (activate each other). Activated JAKs phosphorylate the receptor tails, creating docking sites for STAT proteins (Signal Transducers and Activators of Transcription). STATs get phosphorylated, dimerize, and move to the nucleus to regulate gene expression.

JAK/STAT signaling

Promotes cell proliferation, survival, and immune regulation.

Constitutive activation of JAK or STAT

Causes constant transcription of growth and survival genes. Seen in leukemias, lymphomas, and some solid tumors.

TGF-β Receptors

Two types: Type I and Type II serine/threonine kinase receptors. Each has an extracellular ligand-binding domain, a transmembrane domain, and a cytoplasmic kinase domain.

Activation of TGF-β Receptors

TGF-β ligand (a dimer) binds to the Type II receptor. Type II receptor recruits and phosphorylates the Type I receptor. Activated Type I receptor phosphorylates SMAD2/3 proteins in the cytoplasm. SMAD2/3 bind SMAD4 → complex moves into the nucleus. Regulates genes controlling cell cycle arrest, differentiation, and ECM production.

TGF-β / SMAD signaling

Normally inhibits epithelial cell growth (tumor suppressor).

Loss of TGF-β receptor or SMAD function

Early tumors escape growth inhibition.

Hijacking TGF-β signaling

Later-stage tumors promote EMT (epithelial-mesenchymal transition), invasion, and metastasis.

Frizzled Receptors

7-transmembrane domain receptors. Bind Wnt proteins (lipid-modified glycoproteins). Work with a co-receptor called LRP5/6.

Activation of Frizzled Receptors

Wnt binds Frizzled + LRP5/6. This recruits Dishevelled (Dsh), which inhibits the β-catenin destruction complex (APC, Axin, GSK3β). β-catenin accumulates in the cytoplasm. β-catenin enters the nucleus and activates Wnt target genes that control proliferation and stemness.

Wnt / β-catenin signaling

Controls development, differentiation, and cell fate.

Mutations in APC or β-catenin

Prevent its degradation → constant activation. Drives colon, liver, and breast cancers by promoting proliferation and loss of differentiation.

GPCRs (G-Protein-Coupled Receptors)

7-transmembrane helices spanning the plasma membrane. Coupled to heterotrimeric G-proteins (α, β, γ subunits) on the cytoplasmic side.

Activation of GPCRs

Ligand (like epinephrine, prostaglandin, or chemokine) binds the extracellular domain. GPCR changes shape → Gα subunit exchanges GDP for GTP. Gα-GTP and Gβγ subunits dissociate and activate downstream effectors: Adenylyl cyclase → cAMP → activates PKA; Phospholipase C (PLC) → IP₃ + DAG → IP₃ releases Ca²⁺, DAG activates PKC. These second messengers regulate gene expression, metabolism, and cytoskeletal activity.

cAMP/PKA pathway

One of the pathways activated by GPCRs.

IP₃/DAG/PKC pathway

Another pathway activated by GPCRs.

Calcium signaling

A pathway activated by GPCRs.

Mutations or overexpression of GPCRs or G-proteins

Cause ligand-independent activation. Leads to uncontrolled growth, angiogenesis, migration, and metastasis. Common in melanoma, thyroid, and endocrine tumors.

Integrins

Heterodimers are made up of one α and one β subunit. Span the plasma membrane, connecting the extracellular matrix (ECM) to the cytoskeleton.

Activation of Integrins

Integrins bind ECM proteins like fibronectin, laminin, or collagen. Ligand binding causes integrin clustering, recruiting FAK (Focal Adhesion Kinase) and Src kinases. These activate downstream pathways such as MAPK and PI3K/Akt, which control survival and motility.

FAK/Src signaling

Often linked to MAPK and PI3K/Akt pathways.

Overexpression or abnormal activation of Integrins

Enhances cell migration, invasion, and survival. Integrins also cooperate with RTKs, helping tumor cells resist apoptosis and detach to metastasize.

Immediate early genes

Genes activated within minutes after growth factor signaling - no new protein synthesis needed.

Delayed early genes

Required protein synthesis (they need to make transcription factors) of IEG products (like Fos/Jun) to be expressed.

Bridging/adapter proteins

They are connectors between the receptor on the cell surface and the inside signaling molecule.

SH2

A small part of a protein that can recognize and stick to phosphorylated tyrosines (P-Try) on activated receptors.

SH3

A domain that can bind to proline-rich regions on other proteins (like SOS).

Ras effectors

Once Ras is turned on (bound to GTP) it passes the message to effector proteins.

Mitogen-activated protein kinase signaling pathway

The stimulus (Growth factors, Mitogens, GPCR) → MAPKK (A-Rad, b-Rad, C-raf, Mos, TpI2) → MAPKK (MEK ½) → MAPK (Erk ½) → Biological Response (Growth, differentiation, Development).

Phosphatases

These are opposite of kinases (remove phosphate group and turn signal off).

Anoikis

A type of cell death that happens when cells lose contact with the ECM.

c-Fos

An example of an immediate early gene.

c-Jun

An example of an immediate early gene.

Myc

An example of an immediate early gene.

Grb2

An example of a bridging/adapter protein.

Shc

An example of a bridging/adapter protein.

SOS

An example of a bridging/adapter protein.

Raf

Starts the MAPK pathway (controls growth and division).

PI3k

Activates Akt (keeps cells alive and helps them grow).

Ral-GEFs

Control cell movement and vesicle transport.

PTEN

A phosphatase that stops PI3K/Akt signaling.

Serum

Contains growth factors.

G0 phase

A resting phase where there is no DNA replication, low metabolism, and no new RNA synthesis.

Delayed genes

Genes that turn on later, pushing the cell into the cell cycle.

CHX

Blocks protein synthesis; immediate early genes turn on but delayed genes do not.

Receptor phosphorylation

Occurs within minutes of serum addition, initiating early signaling.

MAPK

A signaling pathway activated during early signaling after serum addition.

DNA synthesis

Begins 1-2 hours after serum addition when delayed genes start transcription.

Cell cycle re-entry

Over time, the cell becomes larger, more metabolically active, and resumes division.

Ras activation

Occurs when GF binds to receptor tyrosine kinase, leading to a series of phosphorylation events.

PI3K → Akt

Activated by Ras; promotes cell growth and survival, prevents cell death.

Raf → MAPK

Activated by Ras; causes cell proliferation and differentiation.

Ral → GEF

Activated by Ras; controls movement, vesicle trafficking, and cytoskeletal changes.

Jak/STST pathway

Activated when a cytokine binds to its receptor, leading to gene activation for growth and survival.

Integrin signaling

Senses attachment to the ECM and sends two-way signals affecting cell survival and movement.

TGF-B signaling cascade

Involves TGF-B binding to receptors, activating SMAD proteins, and regulating cell functions.

Stages of cell signaling

Reception: ligand binds to receptor; Transduction: signal is passed along; Response: the cell reacts.

Cancer therapeutics design

Involves targeting receptors, kinase activity, signaling pathways, helper proteins, and gene expression.

Trastuzumab

Binds HER2, blocking activation.

Lapatinib

Targets EGFR/HER2 kinase activity.

RAF inhibitors

Such as Sorafenib, block pathways downstream of Ras.

Cytotoxic drugs

Used to target uncontrolled cell proliferation.

What is interphase?

The growth and preparation period before cell division, including G1, S, and G2 phases.

What is the G0 phase?

A nondividing stage where a cell exits the cycle permanently or temporarily.

What are cell cycle checkpoints?

Surveillance mechanisms ensuring DNA integrity and proper replication before progression.

What happens if DNA replication is not completed?

Entrance into mitosis is blocked.