Signal Transduction
FIG 21.32 Regulation of glycogenolysis in liver: allosteric inhibition of PP1c by activated phosphorylase. In liver, both glycogen phosphorylase and PP1c bind the regulatory subunit GL (distinct from GM in muscle).
PKA phosphorylates and activates phosphorylase kinase, and phosphorylates and inactivates glycogen synthase
(1). Phosphorylase kinase then phosphorylates and activates glycogen phosphorylase (2), which then sterically hinders the adjacent PP1 (3). Glycogen breakdown ensues.
glycogen phosphorylase. (This gathering together of both enzymes does not operate for the much larger GM.) Again, this provides an effective means for coupling the activation of glycogenolysis to the inhibition of glycogen synthesis, and vice versa.
PP2B (calcineurin)
Although we now recognize that PP2B has a wide tissue distribution,140 it is identical to a Ca2 -binding protein that was originally identified in neural
tissue and named calcineurin.141 Some time after its discovery, it was realized that calcineurin possesses phosphatase activity and that one of its regulatory subunits is the Ca2 -binding protein calmodulin. The functional protein actually consists of three subunits: calcineurin A (CnA, the catalytic subunit), calcineurin B (CnB, a Ca2 -binding, calmodulin-like subunit), and calmodulin. The principal role of CnB appears to be structural. The phosphatase activity of CnA is activated by Ca2 (see page 230).
682
Protein Dephosphorylation and Protein Phosphorylation
Dephosphorylation of NFAT: immunophilins show the way
Functional roles of calcineurin have come to light through the use of drugs that bind to cytosolic proteins called immunophilins. This name reflects the circumstances of their discovery. In 1972, cyclosporin A (now ciclosporin), a fungal product, was found to have remarkable immunosuppressive properties and few side effects.142 It is effective in preventing transplant rejection and graft versus host disease. Indeed, since its discovery, the use of ciclosporin A has enormously increased the life expectancy of patients receiving kidney, heart, and liver transplants. It also finds application in the treatment of autoimmune diseases and asthma.143 It was nearly 10 years before the cellular target of ciclosporin A was identified as the cytosolic protein cyclophilin A (CypA). Later, another more potent immunosuppressive drug of fungal origin, tacrolimus or FK506, was discovered. It targets the cytosolic binding protein FKBP12. CypA and FKBP12 are called immunophilins and are members of large protein families. The complexes of both tacrolimus and ciclosporin A with their respective target proteins inhibit calcineurin by hindering substrate access144 (Figure 21.33 and Figure 8.4, page 230).
FIG 21.33 Immunophilins bound to their ligand inhibit the phosphatase activity of calcineurin. Under resting conditions calcineurin is in an autoinhibited state in which the C-terminus interferes with the access of substrate. Antigen stimulation causes an increase in cytosolic free Ca2 which binds to the regulatory domains CnB and calmodulin (pink), thereby making the catalytic site available for substrate. In the context of T cell activation, an important substrate is the transcription factor NFAT2, from which numerous phosphates are removed. This exposes the nuclear localization signal. Tacrolimus (not shown) allows the attachment of FKBP12 to the calcineurin complex and this blocks phosphatase activity. See also Figure 8.4, page 230.
Tacrolimus (FK506), a macrolide derived from
Streptomyces, inhibits peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506-binding protein). The FKBP12–tacrolimus complex interacts with and inhibits calcineurin, thus inhibiting both
T lymphocyte signal transduction and IL-2 transcription. Tacrolimus is widely used in the prevention of organ rejection after transplant surgery. Its activity
is similar to that of ciclosporin A.
683
Signal Transduction
One important consequence of the inhibition of calcineurin is the failure of
T cell activation after engagement of the TCR with antigen, presented in MHCcontext (see Figure 17.5, page 519). This arises from the failure of calcineurin to dephosphorylate NFAT transcription factors in preparation for transfer into the nucleus. Inhibition by ciclosporin A or tacrolimus causes abrupt arrest of the TCR signal145 and suppression of the immune response.
List of Abbreviations
Abbreviation |
Full name/description |
SwissProt entry |
Other names/OMIM |
|
|
|
|
AKAP220 |
A-kinase anchoring protein 220 kDa |
Q9UKA4 |
AKAP11 |
|
|
|
|
Bsk |
basket (Drosophila, MAPkinase |
P92208 |
|
|
involved in dorsal closure) |
|
|
|
|
|
|
Bcl-2 |
B cell lymphoma protein-2 |
P10415 |
|
|
|
|
|
C1-TEN |
C1 domain containing tensin-like |
Q8NFF9 |
(splice variant a) |
|
protein |
|
|
|
|
|
|
CD-3 |
cluster of differentiation-3 gamma |
P20963 |
|
|
chain |
|
|
|
|
|
|
CD45 |
cluster of differentiation-45 |
P08575 |
PTPRC |
|
|
|
|
Cdc14A |
cell division cycle-14 homologue A |
Q9UNH5 |
|
|
|
|
|
cdc25b |
cell cycle division-25b |
P30305 |
|
|
|
|
|
CnA |
calcineurin A |
Q08209 |
PP2B, PPP3CA |
|
|
|
|
CnB |
calcineurin B |
P63098 |
PPP3R1 |
|
|
|
|
Cytochrome b |
glycoprotein 91 kDa of phagocyte |
P04839 |
NADPH oxidase, cytochrome |
|
NADPH-oxidase |
|
b245, NOX2 |
|
|
|
|
DEP1 |
density enhanced tyrosine |
Q12913 |
PTPRJ, RPTPh |
|
phosphatase-1 |
|
|
|
|
|
|
DJ-1 |
Daisuke and Junko (names of |
Q99497 |
Parkinson disease protein-7 |
|
students) |
|
(PARK7), MIM:606324 |
|
|
|
|
Dos |
daughter of sevenless (Drosophila, |
Q9VZZ9 |
|
|
positioned in between sevenless |
|
|
|
and dras) |
|
|
|
|
|
|
DUSP |
dual specificity protein phosphatase |
|
|
|
(family) |
|
|
|
|
|
|
ERBB2 |
erythroblastoma protein-2 (EGF |
P04626 |
|
|
receptor) |
|
|
Continued
684
Protein Dephosphorylation and Protein Phosphorylation
Abbreviation |
Full name/description |
SwissProt entry |
Other names/OMIM |
|
|
|
|
Fc RIIB |
low affinity Fc-receptor IIB |
P31994 |
CD32 |
|
|
|
|
FYVE |
Fab1-YOTB-Vac-EEA1 domain (Zn2 - |
|
|
|
finger) |
|
|
|
|
|
|
Gab1 |
Grb2-associated binder 1 |
Q13480 |
|
|
|
|
|
GL |
protein phosphatase 1 glycogen- |
Q86XI6 |
PPP1R3B |
|
targeting subunit in liver |
|
|
|
|
|
|
GM |
protein phosphatase 1 glycogen- |
Q16821 |
protein phosphatase-1 |
|
targeting subunit in muscle |
|
regulatory subunit 3A (PPP1RA), |
|
|
|
PTG |
|
|
|
|
HD-PTP |
histidine-rich domain containing |
Q9H3S7 |
PTPN23 |
|
protein tyrosine phosphatase |
|
|
|
|
|
|
HE-PTO |
haematopoietic protein tyrosine |
P35236 |
PTPN7 |
|
phosphatase |
|
|
|
|
|
|
HGFR |
hepatocyte growth factor receptor |
P08581 |
scatter factor, c-Met |
|
|
|
|
hVH5 |
human VRH-homologous tyrosine |
Q13202 |
DUSP8 |
|
phosphatase-5 |
|
|
|
|
|
|
hYVH1 |
orthologue of S. cerevisiae YVH1 |
Q9UNI6 |
DUSP12 |
|
protein |
|
|
|
|
|
|
I-1 |
inhibitory protein-1 |
Q13522 |
IPP-1, PPP1R1A |
|
|
|
|
IA2 |
islet-cell autoantigen-regulated |
Q92932 |
PTPRN2 |
|
protein-2 |
|
|
|
|
|
|
IFNAR1 |
interferon-alpha receptor-1 |
P17181 |
|
|
|
|
|
IL-R |
interleukin receptors |
|
|
|
|
|
|
ITIM |
immunoreceptor tyrosine-based |
|
|
|
inhibition motif |
|
|
|
|
|
|
JAK2 |
Janus kinase-2 |
O60674 |
|
|
|
|
|
JSP-1 |
JNK-stimulatory phosphatase-1 |
Q9NRW4 |
DUSP22 |
|
|
|
|
KAP-1 |
CDK-asociated dual specificity |
Q16667 |
CDKN3 (cylin dependent kinase |
|
phosphatase |
|
inhibitor-3) |
|
|
|
|
KIR |
killer-cell inhibitory receptor (many |
|
|
|
subtypes) |
|
|
|
|
|
|
Laforin |
lafora-type myoclonus epilepsy |
O95278 |
EPM2A (epilepsy myoclonus) |
Continued
685
Signal Transduction
Abbreviation |
Full name/description |
SwissProt entry |
Other names/OMIM |
|
|
|
|
LAR |
leukocyte antigen related protein |
P10586 |
PTPRF |
|
|
|
|
LMW-PTP |
low molecular weight PTP |
P24666 |
red cell acid phosphatase-1 |
|
|
|
(ACP1) |
|
|
|
|
Lyn |
Lck/Yes-related novel tyrosine kinase |
P07948 |
|
|
|
|
|
MCE |
mRNA capping enzyme |
O60942 |
RNGTT (mRNA |
|
|
|
guanylyltransferase) |
|
|
|
|
MEG2 |
megakaryocyte protein tyrosine |
P43378 |
PTPN9, homology with |
|
phosphatase-2 |
|
retinaldehyde-binding protein |
|
|
|
SEC14 |
|
|
|
|
Met |
methyl-nitro-nitroguanidine- |
P08581 |
scatter factor, hepatocyte growth |
|
induced oncogene |
|
factor receptor |
|
|
|
|
MKP3 |
MAPkinase phosphatase-3 |
|
DUSP6, Pyst1 |
|
|
|
|
MK-Styx |
MAPK phosphatase serine/ |
Q9Y6J8 |
DUSP24 |
|
threonine/tyrosine interacting like |
|
|
|
protein |
|
|
|
|
|
|
MTM1 |
myotubular myopathy |
Q13496 |
myotubularin |
|
|
|
|
MTMR3 |
MTM-related protein-3 |
Q13615 |
ZFYVE10 (Zn finger FYVE domain |
|
|
|
protein) |
|
|
|
|
MTMR6 |
MTM-related protein-6 |
Q9Y217 |
|
|
|
|
|
MTMR10 |
MTM-related protein-10 |
Q6P4Q6 |
truncated |
|
|
|
|
MTMR13 |
MTM-related protein-13 |
Q86WG5 |
SET-binding factor2 (SBF2) |
|
|
|
|
MYPT1 |
myosin phosphatase 1 target |
O14974 |
PPP1R12A, M110, smooth muscle |
|
subunit-1 |
|
|
|
|
|
|
MYPT2 |
myosin phosphatase 1 target |
O60237 |
PPP1R12B, skeletal muscle |
|
subunit-2 |
|
|
|
|
|
|
NFAT2 |
nuclear factor of activated T cells 2 |
O95644 |
NFATc1, NFATc |
|
|
|
|
NIPP1 |
nuclear inhibitor of protein |
Q12972 |
PPP1R8 |
|
phosphatase-1 |
|
|
|
|
|
|
Noonan |
|
MIM 163950 |
|
syndrome |
|
|
|
|
|
|
|
NOX1 |
NADPH-oxidase homologue 1 |
Q9Y5S8 |
mitogenic oxidase |
|
|
|
|
NOXA |
NOX activator |
P19878 |
p67 |
|
|
|
|
Continued
686
Protein Dephosphorylation and Protein Phosphorylation
Abbreviation |
Full name/description |
SwissProt entry |
Other names/OMIM |
|
|
|
|
NOXO1 |
NOX organizer-1 |
Q8NFA2 |
p41NOX (PX domain protein) |
|
|
|
|
OB-R |
obese receptor |
P48357 |
leptin receptor |
|
|
|
|
PCPTP1 |
pheochromocytoma-12 (PC12) |
Q15256 |
PTPRR |
|
protein tyrosine phosphatase-1 |
|
|
|
|
|
|
PDP |
mitochondrial pyruvate |
Q9P0J1 |
PMM2C |
|
dehydrogenase phosphatase |
|
|
|
|
|
|
PEP |
PEST domain enriched tyrosine |
Q9Y2R2 |
PTPN22, Lyp (lymphoid |
|
phosphatase |
|
phosphatase) |
|
|
|
|
PIR1 |
phosphatase interacting with RNA/ |
O75319 |
DUSP11 |
|
RNP complex-1 |
|
|
|
|
|
|
PP1c |
serine threonine phosphatase-1 |
P62136 |
PPP1CA |
|
(alpha) catalytic subunit |
|
|
|
|
|
|
PP2a |
serine threonine phosphatase-2 |
P67775 |
PPP2CA |
|
(alpha) catalytic subunit |
|
|
|
|
|
|
PP2B |
serine threonine phosphatase-2 |
Q08209 |
PPP3CA, calcineurin A (CnA) |
|
(beta) catalytic subunit |
|
|
|
|
|
|
PP2C |
serine threonine phoshatase 2C |
P35813 |
PPM1A |
|
isoform alpha |
|
|
|
|
|
|
PP4 |
serine threonine phosphatase-4 |
P60510 |
PPP4C, PP-X |
|
catalytic subunit |
|
|
|
|
|
|
PP4R1 |
PP4 regulatory subunit-1 |
Q8TF05 |
PPP4R1 |
|
|
|
|
PP5 |
serine threonine phosphatase-5 |
P53041 |
PPP5C |
|
catalytic subunit |
|
|
|
|
|
|
PP6 |
serine threonine phosphatase-6 |
O00743 |
PPP6C |
|
catalytic subunit |
|
|
|
|
|
|
PRL1 |
phosphatase of regenerating liver |
Q93096 |
PTP4A, PTPCAAX |
|
|
|
|
PTEN |
phosphatase and tension homology |
P60484 |
mutated in multiple advanced |
|
|
|
cancers-1 (MMAC1) |
|
|
|
|
PTP |
protein tyrosine phosphatase |
|
|
|
|
|
|
PTP1B |
protein tyrosine phosphatase 1B |
P18031 |
PTPN1 |
|
|
|
|
PTP |
protein tyrosine phosphatase-alpha |
P18433 |
PTPRA |
|
|
|
|
PTP-BAS |
protein tyrosine phosphatase |
Q12923 |
PTPN13 |
|
basophil |
|
|
Continued
687
Signal Transduction
Abbreviation |
Full name/description |
SwissProt entry |
Other names/OMIM |
|
|
|
|
PTP-D1 |
protein tyrosine phoshatase distinct |
Q16825 |
PTPN21 |
|
subfamily-1 |
|
|
|
|
|
|
PTP |
protein tyrosine phosphatase- |
P23470 |
PTPRG |
|
gamma |
|
|
|
|
|
|
PTP-H1 |
protein tyrosine phosphatase in |
P26045 |
PTPN3 |
|
human colon-1 |
|
|
|
|
|
|
PTP- |
protein tyrosine phosphatase-mu |
P28827 |
PTPRM |
|
|
|
|
PTP-PEST |
protein tyrosine phosphatase Pro- |
P35831 |
PTPN12 |
|
Glu-Ser-threonine rich sequence |
|
|
|
|
|
|
RP65 |
regulatory protein 65 kDa (subunit |
P30153 |
PPP2R1A |
|
A of PP2a) |
|
|
|
|
|
|
SHP-1 |
Src-homology domain containing |
P29350 |
SH-PTP1, PTPN6, PTP1C |
|
tyrosine phosphatase-1 |
|
|
|
|
|
|
SHP-2 |
Src-homology domain containing |
Q06124 |
SH-PTP2, PTPN11, PTP2C |
|
tyrosine phosphatase-2 |
|
|
|
|
|
|
SOCS1 |
suppressor of cytokine signalling-1 |
O15524 |
|
|
|
|
|
spinophilin |
|
Q96SB3 |
PPP1R9B, neurabin-2 |
|
|
|
|
Src |
sarcoma (soft tissue tumour) |
P12931 |
|
|
|
|
|
SSH1 |
slingshot-homologue-1 |
QWYL5 |
|
|
|
|
|
STAT5 |
signal transducer and activator of |
P42229 |
|
|
transcription-5 |
|
|
|
|
|
|
Styx |
serine/threonine/tyrosine |
Q8WUJ0 |
|
|
interacting like protein |
|
|
|
|
|
|
tensin-1 |
|
Q9HBL0 |
TNS1 |
|
|
|
|
tyk2 |
non-receptor tyrosine kinase-2 |
P29597 |
|
|
|
|
|
VH1 |
vaccinia virus H1 |
|
|
|
|
|
|
VHR |
vaccinia virus phosphatase VH1- |
P51452 |
DUSP3 |
|
related |
|
|
|
|
|
|
688