CellChapter13

Cell Signaling

SIGNALING MOLECULES AND THEIR RECEPTORS:

Signaling Molecules and Their Receptors, Functions of Cell Surface Receptors

Pathways of Intracellular Signal Transduction, Signal Transduction and the Cytoskeleton

Signaling in Development and Differentiation, Regulation of Programmed Cell Death

Key Experiment: The Src Protein-Tyrosine Kinase, Molecular Medicine: Cancer, Signal Transduction, and the ras Oncogenes

Molecules that transmit information between the cells of multicellulor organism. Signalling molecules include simple gases to complex proteins.

Modes of Cell-Cell Signaling: Most signaling molecules are secreted by

one cell and bind to receptors expressed by a target cell. Cell-cell signaling

is divided into three general categories (endocrine, paracrine, and

autocrine signaling) based on the distance over which signals are trans-mitted.

Steroid Hormones and the Steroid Receptor Superfamily: The steroid

hormones, thyroid hormone, vitamin D3 , and retinoic acid are small

hydrophobic molecules that diffuse across the plasma membrane of their

target cells and bind to intracellular receptors. Members of the steroid

receptor superfamily function as transcription factors to directly regu-late

gene expression in response to ligand binding.

Nitric Oxide and Carbon Monoxide: The simple gases nitric oxide and

carbon monoxide are important paracrine signaling molecules in the

nervous system and other cell types.

Neurotransmitters: Neurotransmitters are small hydrophilic molecules

that carry signals between neurons or between neurons and other target

cells at a synapse. Many neurotransmitters bind to ligand-gated ion

channels.

Peptide Hormones and Growth Factors: The widest variety of signaling

molecules in animals are peptides, ranging from only a few to more than

a hundred amino acids. This group of molecules includes peptide hor-mones,

neuropeptides, and growth factors.

Eicosanoids: The eicosanoids are a class of lipids that function in

paracrine and autocrine signaling.

Plant Hormones: Small molecules known as plant hormones regulate

plant growth and development.

FUNCTIONS OF CELL SURFACE RECEPTORS

G Protein-Coupled Receptors: The largest family of cell surface re c ep t o r s ,

i n c l uding the re c eptors for many hormones and neuro t ransmitters, tra n s-mit

signals to intracellular targets via the intermediary action of G pro t e i n s .

Receptor Protein-Tyrosine Kinases: The receptors for most growth fac-tors

are protein-tyrosine kinases.

Cytokine Receptors and Nonreceptor Protein-Tyrosine Kinases: The

receptors for many cytokines act in association with non-receptor protein-

tyrosine kinases.

Receptors Linked to Other Enzymatic Activities: Other kinds of cell surface

receptors include protein-tyrosine phosphatases, protein-serine/

threonine kinases, and guanylyl-cyclases.

PATHWAYS OF INTRACELLULAR SIGNAL TRANSDUCTION
The cAMP Pathway: Second Messengers and Protein Phosphorylation:

Cyclic AMP is an important second messenger in the response of animal

cells to a variety of hormones and odorants. Most actions of cAMP are

mediated by protein kinase A, which phosphorylates both metabolic

enzymes and the transcription factor CREB.

Cyclic GMP: Cyclic GMP is also an important second messenger in ani-mal

cells. Its best-characterized role is in visual reception in the verteb

rate eye.

Phospholipids and Ca 2 + : Phospholipids and Ca²⁺ are known common second

messengers activated downstream of both G pro t e i n - co u pled re c ep t o r s

and pro t e i n - t y rosine kinases. Hydrolysis of phosphatidylinositol 4,5-bis-phosphate

(PIP 2 ) yields diacylglycerol and inositol 1,4,5-tri s p h o s p h a t e

( I P 3 ), which activate protein kinase C and mobilize Ca 2 + f rom intra c e l l u l a r

s t o res, re s p e c t i ve l y. Increased levels of cytosolic Ca 2 + t h en activate a va ri-ety

of target proteins, including Ca 2 + / c a l m o d u l i n - d ep en d ent pro t e i n

kinases. In electrically excitable cells of nerve and muscle, levels of cytoso-lic

Ca 2 + a re increased by the op ening of voltage-gated Ca 2 + channels in the

plasma membrane and ryanodine re c eptors in the en d oplasmic and sar-coplasmic

reticulum. In addition to being cleaved into diacylglycerol and

I P 3 , PIP 2 can be phosphorylated to the distinct second messenger PIP 3 .

Ras, Raf, and the MAP Kinase Pathway: The MAP kinase pathway is a

conserved chain of protein kinases activated downstream of a variety of

extracellular signals. In animal cells, the best-characterized forms of

MAP kinase are coupled to growth factor receptors by the small GTP-binding

protein Ras, which initiates a protein kinase cascade leading to

MAP kinase (ERK) activation. ERK then phosphorylates a variety of

cytosolic and nuclear proteins, including transcription factors that medi-ate

immediate-early gene induction.

The JAK/STAT Pathway: STAT proteins are transcription factors that

contain SH2 domains and are activated directly by protein-tyrosine

kinases associated with cytokine and growth factor receptors.

SIGNAL TRANSDUCTION AND THE CYTOSKELETON

Integrins and Signal Transduction: Binding of integrins to the extra-cellular

matrix stimulates the FAK nonreceptor protein-tyrosine kinase,

leading to activation of MAP kinase and other downstream signaling

pathways.

Regulation of the Actin Cytoskeleton: Growth factors induce alterations

in cell movement and cell shape by remodeling the actin cytoskeleton.

These cytoskeletal alterations are mediated by members of the Rho sub-family

of small GTP-binding proteins.

SIGNALING IN DEVELOPMENT AND DIFFERENTIATION

The Receptor Tyrosine Kinase/Ras/MAPKinase Pathway in Drosophila

and C. elegans: The role of the Ras/Raf/MAP kinase pathway in devel-opment

has been elucidated by studies of the differentiation of photore-ceptor

neurons in Drosophila and vulval induction in C. elegans.

Hedgehog and Wingless: The Hedgehog and Wingless signaling path-ways

play key roles in determination of cell fate and patterning during

development of both invertebrate and vertebrate embryos.

Notch Signaling: The Notch pathway controls cell fate by direct cell-cell

interactions during animal development.

REGULATION OF PROGRAMMED CELL DEATH

Caspases and Apoptosis: Programmed cell death plays a key role both

in the maintenance of adult tissues and embryonic development. Compare

to the accidental death of cells from an acute injury, programmed

cell death takes place by the active process of apoptosis. Some genes are responsible

for the regulation and execution of apoptosis are conserved from C.

elegans to humans. These components of the cell death machinery

include a family of protease enzyme (known as caspases) that are the effectors of apoptosis mechanism

as well as proteins that regulate caspase activation.

Cell Death Receptors and Caspase Activation: Some secreted poly-peptides

Play role in inducing programmed cell death by activating receptors that are

directly linked to caspases.

Signaling Cell Survival: Many cells are dependent on survival signals

from secreted factors or cell-cell contacts that are known to suppress apoptosis. The PI

3-kinase/Akt pathway is a major signaling pathway responsible for promoting

cell survival.

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