Test 4. Lecture 33

Question 1

_______________ stimulate intracellular tyrosine kinases
with which they are noncovalently associated.

The ____________includes receptors for most
cytokines and some polypeptide hormones.

The structure of cytokine receptors is similar to receptor tyrosine
kinases, but the cytosolic domains have no catalytic activity.

 Ligand binding induces _____________ and CROSS PHOSPHORYLATION OF ASSOCIATED NONRECEPTOR TYROSINE KINASES

 The activated kinases then phosphorylate the receptor.

 This provides phosphotyrosine-binding sites for recruitment of
downstream signaling molecules with SH2 domains.

Answer 1

Nonreceptor tyrosine kinases

cytokine receptor superfamily

dimerization of receptors

Question 2

describe MAP Kinase pathway:

Answer 2

The MAP kinase pathway is a cascade of protein kinases that is highly
conserved in evolution, found in all eukaryotic cells

Question 3

what are MAP kinases?

Answer 3

(mitogen-activated protein kinases) are serine/threonine

kinases.

Question 4

MAP kinases initially found in mammalian cells belong to the ________
(extracellular signal-regulated kinase) family

Answer 4

ERK

Question 5

The role of ERK signaling emerged from studies of _________ proteins, first identified as the oncogenic proteins of viruses that cause sarcomas in
rats

Answer 5

Ras

Question 6

What are ras protiens?

Answer 6

are guanine
nucleotide-binding proteins that alternate between
inactive GDP-bound and active GTP-bound forms.

Question 7

Ras is activated by ____________ that stimulate exchange of GDP for GTP.

Answer 7

guanine nucleotide exchange

factors (GEFs)

Question 8

Ras-GTP activity is terminated
by GTP hydrolysis,
stimulated by interaction of Ras-GTP with ______________

Answer 8

GTPaseactivating

proteins (GAPs)

Question 9

Mutations of ras genes in cancers inhibit_________, so the Ras proteins
remain continuously in the active GTP-bound form, driving proliferation of
cancer cells.

Answer 9

GTP hydrolysis

Question 10

Autophosphorylation of receptor tyrosine kinase receptors leads to binding
of Ras GEFs.

GEFs interact with Ras proteins and stimulate exchange of GDP for GTP,
forming the active Ras-GTP complex.

of Ras leads to activation of ______ protein serine/threonine
kinase.
Raf phosphorylates and activates a second protein kinase, MEK (_____________).

ERK phosphorylates a variety of target proteins.

Answer 10

Raf

MAP
kinase/ERK kinase

Question 11

Some activated ERK goes to the
___________, where it regulates
transcription factors by
phosphorylation.

Answer 11

nucleus

Question 12

A primary response to growth factor stimulation is rapid transcription of
___________.

This is mediated by a regulatory sequence called the_______________, which is recognized by transcription factors including the
serum response factor (_________) and __________

Many immediate-early genes encode transcription factors.

Their induction leads to altered expression of a battery of other downstream
genes called ______________.

Answer 12

immediate-early genes

serum response
element (SRE),

SRF and Elk-1

secondary response genes

Question 13

Yeasts and mammalian cells have multiple MAP kinasepathways.

Each cascade consists of three protein kinases: a _________ and___________
(analogous to Raf and
MEK).

Mammalian MAP kinases
include ERK, JNK, and
p38 kinases.

Answer 13

terminal MAP kinase

two upstream kinases

Question 14

Specificity of MAP kinase signaling is maintained partly by physical association on ____________

Example: KSR scaffold protein
organizes ERK and its
upstream activators Raf and
MEK into a signaling
cassette.

Answer 14

scaffold proteins.

Question 15

PI 3-kinase/Akt pathway:

Based on a second messenger derived from the membrane phospholipid
_____________________

Answer 15

phosphatidylinositol 4,5-bisphosphate (PIP2

).

Question 16

PIP2 is phosphorylated by ___________3-kinase to yield

the second messenger _______________

Answer 16

phosphatidylinositide (PI)

phosphatidylinositol 3,4,5-trisphosphate
(PIP3).

Question 17

1. PI 3-kinase is recruited to activated receptor tyrosine kinases via its
   SH2 domain.
2. PIP3
   targets a serine/threonine kinase called __________via its pleckstrin
   homology (PH) domain.
3. Akt is phosphorylated and activated by another protein kinase (PDK1).
4. Activation of Akt also requires phosphorylation by protein kinase
   mTORC2, which is also stimulated by growth factors

Answer 17

Akt

Question 18

Phospholipase C/Calcium Pathway:

Hydrolysis of PIP2 by PHOSPHOLIPASE C
produces two second messengers:

Answer 18

• Diacylglycerol (DAG)
• Inositol 1,4,5-trisphosphate
(IP3)

Phospholipase C-γ (PLC-γ) binds to
activated receptor

tyrosine kinases via
its SH2 domains.
Tyrosine phosphorylation increases
PLC- γ activity, stimulating hydrolysis
of PIP2
.
DAG and IP3 stimulate downstream
pathways.

Question 19

DAG remains associated with the plasma membrane and activates
serine/threonine kinases of the __________family.

IP3 binds to receptors that are ligandgated
Ca2+ channels in the ER.
Opening these channels allows
Ca2+ to move out of the ER.

One of the major Ca2+-binding proteins that mediates the effects of
Ca2+ is ________, which is activated when Ca2+ concentration
increases.

Ca2+/calmodulin then binds to target
proteins, including protein kinases.

Answer 19

protein kinase C

calmodulin

Question 20

In NONMUSCLE cells and SMOOTH MUSCLE, contraction is regulated primarily by
___________ of a myosin light chain.

It is catalyzed by ______________, which is regulated by
the Ca2+-binding protein __________

Answer 20

phosphorylation

myosin light chain kinase (MLCK)

calmodulin.

Question 21

1. ONE EXAMPLE OF A Ca2+/calmodulin-DEPENDENT PROTEIN KINASE is myosin lightchain
   kinase, which signals actin-myosin contraction by phosphorylating one of
   the myosin light chains.
2. Members of the _________ family are also activated by Ca2+/calmodulin.
   They phosphorylate metabolic enzymes, ion channels, and transcription factors.
   One form of CaM kinase regulates synthesis and release of neurotransmitters.
   CaM kinases can also regulate gene expression by phosphorylating transcription
   factors.
   CREB is phosphorylated by CaM kinase and also by protein kinase A.
   This illustrates one of many intersections between the Ca2+ and cAMP signaling
   pathways, which function coordinately to regulate many cellular responses.
   Figure 16.17 Cyclic AMP-induc

Answer 21

CaM kinase

Question 22

Phosphorylation of CREB
leads to recruitment of
coactivators and
expression of cAMPinducible
genes.

Regulation of gene
expression by cAMP plays
important roles in many
aspects of cell behavior.

Answer 22

General informatinon

Question 23

Ca2+ is also increased by uptake of
extracellular Ca2+ by regulated
channels in the plasma
membrane.

In electrically excitable cells of nerve
and muscle, voltage-gated Ca2+
channels are opened by
membrane depolarization.

The resulting increase in intracellular
Ca2+ signals further release of
Ca2+ from the ER by opening Ca2+
channels (\_\_\_\_\_\_\_\_\_\_\_\_-)
in the ER membrane.

One effect of higher Ca2+ is to trigger
release of neurotransmitters.

Answer 23

ryanodine receptors

Question 24

In muscle cells, ryanodine receptors in the SR may also be opened directly
in response to membrane depolarization.

________ is a versatile second messenger that controls a wide range of cellular
processes.

Several other types of growth factor receptors are directly coupled to
transcription factors

Answer 24

Ca2+