1. Principles of Cell Signaling By Melanie H. Cobb & Elliott M. Ross
Chapter 14
Principles of Cell Signaling By
Melanie H. Cobb & Elliott M. Ross

2. 14.2 Cellular signaling is primarily chemical
Cells can detect both chemical and physical signals.
Physical signals are generally converted to chemical signals at the level of the receptor.

3. 14.3 Receptors sense diverse stimuli but initiate a limited repertoire of cellular signals
Receptors contain:
a ligand-binding domain
an effector domain
Receptor modularity allows a wide variety of signals to use a limited number of regulatory mechanisms.

4. Cells may express different receptors for the same ligand.
14.3 Receptors sense diverse stimuli but initiate a limited repertoire of cellular signals
Cells may express different receptors for the same ligand.
The same ligand may have different effects on the cell depending on the effector domain of its receptor.

5. 14.4 Receptors are catalysts and amplifiers
Receptors act by increasing the rates of key regulatory reactions.
Receptors act as molecular amplifiers.

6. 14.5 Ligand binding changes receptor conformation
Receptors can exist in active or inactive conformations.
Ligand binding drives the receptor toward the active conformation.

7. 14.6 Signals are sorted and integrated in signaling pathways and networks
Signaling pathways usually have multiple steps and can diverge and/or converge.
Divergence allows multiple responses to a single signal.
Convergence allows signal integration and coordination.

8. 14.7 Cellular signaling pathways can be thought of as biochemical logic circuits
Signaling networks are composed of groups of biochemical reactions.
The reactions function as mathematical logic functions to integrate information.
Combinations of such logic functions combine as signaling networks to process information at more complex levels.

9. 14.8 Scaffolds increase signaling efficiency and enhance spatial organization of signaling
organize groups of signaling proteins
may create pathway specificity by sequestering components that have multiple partners

10. Scaffolds increase the local concentration of signaling proteins.
14.8 Scaffolds increase signaling efficiency and enhance spatial organization of signaling
Scaffolds increase the local concentration of signaling proteins.
Scaffolds localize signaling pathways to sites of action.

11. 14.9 Independent, modular domains specify protein-protein interactions
Protein interactions may be mediated by small, conserved domains.
Modular interaction domains are essential for signal transmission.
Adaptors consist exclusively of binding domains or motifs.

12. 14.10 Cellular signaling is remarkably adaptive
Sensitivity of signaling pathways is regulated to allow responses to change over a wide range of signal strengths.
Feedback mechanisms execute this function in all signaling pathways.

13. 14.10 Cellular signaling is remarkably adaptive
Most pathways contain multiple adaptive feedback loops to cope with signals of various strengths and durations.

14. 14.11 Signaling proteins are frequently expressed as multiple species
Distinct species (isoforms) of similar signaling proteins expand the regulatory mechanisms possible in signaling pathways.

15. Isoforms may differ in:
14.11 Signaling proteins are frequently expressed as multiple species
Isoforms may differ in:
function
susceptibility to regulation
expression
Cells may express one or several isoforms to fulfill their signaling needs.

16. 14.12 Activating and deactivating reactions are separate and independently controlled
Activating and deactivating reactions are usually executed by different regulatory proteins.
Separating activation and inactivation allows for fine-tuned regulation of amplitude and timing.

17. 14.13 Cellular signaling uses both allostery and covalent modification
Allostery refers to the ability of a molecule to alter the conformation of a target protein when it binds noncovalently to that protein.
Modification of a protein’s chemical structure is also frequently used to regulate its activity.

18. 14.14 Second messengers provide readily diffusible pathways for information transfer
Second messengers can propagate signals between proteins that are at a distance.
cAMP and Ca2+ are widely used second messengers.

19. 14.15 Ca2+ signaling serves diverse purposes in all eukaryotic cells
Ca2+ serves as a second messenger and regulatory molecule in essentially all cells.

20. Ca2+ acts directly on many target proteins.
14.15 Ca2+ signaling serves diverse purposes in all eukaryotic cells
Ca2+ acts directly on many target proteins.
It also regulates the activity of a regulatory protein calmodulin.
The cytosolic concentration of Ca2+ is controlled by organellar sequestration and release.

21. 14.16 Lipids and lipid-derived compounds are signaling molecules
Multiple lipid-derived second messengers are produced in membranes.
Phospholipase Cs release soluble and lipid second messengers in response to diverse inputs.

22. PI 3-kinase synthesizes PIP3 to modulate cell shape and motility.
14.16 Lipids and lipid-derived compounds are signaling molecules
Channels and transporters are modulated by different lipids in addition to inputs from other sources.
PI 3-kinase synthesizes PIP3 to modulate cell shape and motility.
PLD and PLA2 create other lipid second messengers.

23. 14.17 PI 3-kinase regulates both cell shape and the activation of essential growth and metabolic functions
Phosphorylation of some lipid second messengers changes their activity.
PIP3 is recognized by proteins with a pleckstrin homology domain.

24. 14.18 Signaling through ion channel receptors is very fast
Ion channels allow the passage of ions through a pore.
This results in rapid (microsecond) changes in membrane potential.

25. Channels are selective for particular ions or for cations or anions.
14.18 Signaling through ion channel receptors is very fast
Channels are selective for particular ions or for cations or anions.
Channels regulate intracellular concentrations of regulatory ions, such as Ca2+.

26. 14.19 Nuclear receptors regulate transcription
Nuclear receptors modulate transcription by binding to distinct short sequences in chromosomal DNA known as response elements.

27. 14.19 Nuclear receptors regulate transcription
Receptor binding to other receptors, inhibitors, or coactivators leads to complex transcriptional control circuits.
Signaling through nuclear receptors is relatively slow, consistent with their roles in adaptive responses.

28. 14.20 G protein signaling modules are widely used and highly adaptable
The basic module is:
a receptor
a G protein
an effector protein

29. Cells express several varieties of each class of proteins.
14.20 G protein signaling modules are widely used and highly adaptable
Cells express several varieties of each class of proteins.
Effectors are heterogeneous and initiate diverse cellular functions.

30. 14.21 Heterotrimeric G proteins regulate a wide variety of effectors
G proteins convey signals by regulating the activities of multiple intracellular signaling proteins known as effectors.
Effectors are structurally and functionally diverse.

31. Effector proteins integrate signals from multiple G protein pathways.
14.21 Heterotrimeric G proteins regulate a wide variety of effectors
A common G-protein binding domain has not been identified among effector proteins.
Effector proteins integrate signals from multiple G protein pathways.

32. 14.22 Heterotrimeric G proteins are controlled by a regulatory GTPase cycle
Heterotrimeric G proteins are activated when the Gα subunit binds GTP.
GTP hydrolysis to GDP inactivates the G protein.

33. GTP hydrolysis is slow, but is accelerated by proteins called GAPs.
14.22 Heterotrimeric G proteins are controlled by a regulatory GTPase cycle
GTP hydrolysis is slow, but is accelerated by proteins called GAPs.
Receptors promote activation by allowing GDP dissociation and GTP association.
Spontaneous exchange is very slow.
RGS proteins and phospholipase C-βs are GAPs for G proteins.

34. 14.23 Small, monomeric GTPbinding proteins are multiuse switches
Small GTP-binding proteins are:
active when bound to GTP
inactive when bound to GDP
GDP/GTP exchange catalysts known as GEFs (guanine nucleotide exchange factors) promote activation.

35. GAPs accelerate hydrolysis and deactivation.
14.23 Small, monomeric GTPbinding proteins are multiuse switches
GAPs accelerate hydrolysis and deactivation.
GDP dissociation inhibitors (GDIs) slow spontaneous nucleotide exchange.

36. 14.24 Protein phosphorylation/ dephosphorylation is a major regulatory mechanism in the cell
Protein kinases are a large protein family.
Protein kinases phosphorylate:
Ser and Thr
or Tyr
or all three

37. 14.24 Protein phosphorylation/ dephosphorylation is a major regulatory mechanism in the cell
Protein kinases may recognize the primary sequence surrounding the phosphorylation site.
Protein kinases may preferentially recognize phosphorylation sites within folded domains.

38. 14.25 Two-component protein phosphorylation systems are signaling relays
Two-component signaling systems are composed of sensor and response regulator components.

39. 14.25 Two-component protein phosphorylation systems are signaling relays
Upon receiving a stimulus, sensor components undergo autophosphorylation on a histidine (His) residue.
Transfer of the phosphate to an aspartyl residue on the response regulator serves to activate the regulator.

40. 14.26 Pharmacological inhibitors of protein kinases may be used to understand and treat disease
Protein kinase inhibitors are useful both:
for signaling research
as drugs
Protein kinase inhibitors usually bind in the ATP binding site.

41. 14.27 Phosphoprotein phosphatases reverse the actions of kinases and are independently regulated
Phosphoprotein phosphatases reverse the actions of protein kinases.

42. Phosphoprotein phosphatases may dephosphorylate:
14.27 Phosphoprotein phosphatases reverse the actions of kinases and are independently regulated
Phosphoprotein phosphatases may dephosphorylate:
phosphoserine/threonine
phosphotyrosine
or all three
Phosphoprotein phosphatase specificity is often achieved through the formation of specific protein complexes.

43. 14.18 Covalent modification by ubiquitin and ubiquitinlike proteins is another way of regulating protein function
Ubiquitin and related small proteins may be covalently attached to other proteins as a targeting signal.
Ubiquitin is recognized by diverse ubiquitin binding proteins.

44. Ubiquitination can cooperate with other covalent modifications.
14.18 Covalent modification by ubiquitin and ubiquitinlike proteins is another way of regulating protein function
Ubiquitination can cooperate with other covalent modifications.
Ubiquitination regulates signaling in addition to its role in protein degradation.

45. 14.29 The Wnt pathway regulates cell fate during development and other processes in the adult
Seven transmembrane-spanning receptors may control complex differentiation programs.
Wnts are lipid-modified ligands.

46. Wnts signal through multiple distinct receptors.
14.29 The Wnt pathway regulates cell fate during development and other processes in the adult
Wnts signal through multiple distinct receptors.
Wnts suppress degradation of β-catenin, a multifunctional transcription factor.

47. 14.30 Diverse signaling mechanisms are regulated by protein tyrosine kinases
Many receptor protein tyrosine kinases are activated by growth factors.
Mutations in receptor tyrosine kinases can be oncogenic.

48. Ligand binding promotes:
14.30 Diverse signaling mechanisms are regulated by protein tyrosine kinases
Ligand binding promotes:
receptor oligomerization
autophosphorylation
Signaling proteins bind to the phosphotyrosine residues of the activated receptor.

49. 14.31 Src family protein kinases cooperate with receptor protein tyrosine kinases
Src is activated by release of intrasteric inhibition.
Activation of Src involves liberation of modular binding domains for activation-dependent interactions.
Src often associates with receptors, including receptor tyrosine kinases.

50. 14.32 MAPKs are central to many signaling pathways
MAPKs are activated by Tyr and Thr phosphorylation.
The requirement for two phosphorylations creates a signaling threshold.
The ERK1/2 MAPK pathway is usually regulated through Ras.

51. 14.33 Cyclin-dependent protein kinases control the cell cycle
The cell cycle is regulated by cyclin-dependent protein kinases (CDKs).
Activation of CDKs involves:
protein binding
dephosphorylation
phosphorylation

52. 14.34 Diverse receptors recruit protein tyrosine kinases to the plasma membrane
Receptors that bind protein tyrosine kinases use combinations of effectors similar to those used by receptor tyrosine kinases.
These receptors often bind directly to transcription factors.