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Extracellular signaling molecules (growth factors, hormones, neurotransmitters) bind to cell surface receptors, initiating intracellular signaling cascades. Receptor tyrosine kinases (RTKs) dimerize upon ligand binding, autophosphorylate their cytoplasmic tails, and recruit adapter proteins (Grb2) to activate downstream kinases (Ras, MAPK/ERK cascade). GPCRs activate heterotrimeric G proteins (Gs, Gi/o, Gq/11, G12/13), which modulate second messengers (cAMP, IP3, DAG, Ca²⁺). These pathways regulate gene expression, enzyme activity, and cell behavior (proliferation, differentiation, apoptosis).
Cell signaling solves a fundamental problem: how do large, charged, water-soluble molecules like hormones communicate instructions to the cell interior without physically entering the cell? The answer is a relay system. An extracellular signal (the first messenger) binds to a receptor on the cell surface, and the receptor translates that binding event into an intracellular signal (second messenger or protein phosphorylation) that spreads through the cytoplasm and nucleus.
Receptor tyrosine kinases (RTKs) are one major class of receptor. They span the plasma membrane and have a kinase domain on their cytoplasmic tail. When a ligand (like epidermal growth factor or insulin) binds, it forces two receptor monomers together into a dimer. The two kinase domains are now close enough to phosphorylate each other on tyrosine residues — a process called autophosphorylation. These phosphotyrosines act as molecular docking stations for adapter proteins like Grb2, which in turn recruit nucleotide exchange factors that activate Ras. Ras then triggers the MAPK/ERK kinase cascade, ultimately phosphorylating transcription factors and altering gene expression. The whole pathway is essentially a chain of "pass the phosphate" events.
GPCRs operate differently. They are seven-transmembrane proteins coupled to a heterotrimeric G protein (α, β, γ subunits) on the cytoplasmic face. When a ligand binds, the receptor changes shape and catalyzes exchange of GDP for GTP on the Gα subunit, causing Gα to dissociate and diffuse to its effector. Gαs activates adenylyl cyclase, which produces cAMP; Gαi inhibits it; Gαq activates phospholipase C, which generates IP3 and DAG. IP3 releases Ca²⁺ from the endoplasmic reticulum; DAG activates protein kinase C. Each of these second messengers is rapidly degraded (cAMP by phosphodiesterases; Gα self-inactivates by hydrolyzing GTP to GDP), so the signal is transient.
The key concept unifying both pathways is amplification. A single receptor-ligand binding event does not directly cause the cellular response — it sets off a chain reaction where each step generates more activated molecules than the last. One RTK phosphorylates many Ras; one active Ras activates many Raf; each Raf phosphorylates many MEK; each MEK phosphorylates many ERK. This enzymatic cascade means that picomolar concentrations of a hormone can produce a robust cellular response. The tradeoff is complexity: each step is a potential point of failure (cancer mutations often hit Ras or B-Raf) and requires tight regulation.