Variable Type Variable name
External EGlu,EGln,EAsp,
metabolite EGly,EAla,EAsn,
EArg,ESer,ECys,
EHis,EThr,ETrp,
EPhe,EVal,EMet,
ELeu,EIle,ETyr,
EPro,ELys
ENH3
Internal IGlu,IGln,IAsp,
metabolite IGly,IAla,IAsn,
IArg,ISer,ICys,
Ihis,IThr,ITrp,
IPhe,IVal,IMet,
ILeu,IIle,ITyr,Ipro
INH3
IAlphaKetoGlutarate
IHomoCytrate
IAlphaASAA
ILys
biosynthesis regulation
mRNA GCN2m
GCN4m
LYS14m
MKS1m
active protein GCN2ap
GCN4ap
LYS14ap
MKS1ap
Translation Initiation complex
mRNA GCN3m
GCD1m
GCD6m
GCD7m
GCD2m
GCD11m
SUI2m
SUI3m
GCN20m
GCN1m
active Protein GCN3ap
GCD1ap
GCD6ap
GCD7ap
GCD2ap
GCD11ap
SUI2ap
SUI3ap
GCN20ap
GCN1ap
Lysine biosynthesis pathway enzymes
mRNA LYS1m
LYS2m
LYS4m
LYS5m
LYS9m
LYS12m
LYS20m
LYS21m
YJL200Cm
active Protein LYS1ap
LYS2ap
LYS4ap
LYS5ap
LYS9ap
LYS12ap
LYS20ap
LYS21ap
YJL200Cap
Permeases
mRNA GAP1m
CAN1m
PUT4m
MUP3m
DIP5m
SAM3m
AGP3m
MUP1m
HIP1m
APL1m
MMP1m
AGP2m
LYP1m
AGP1m
GNP1m
TAT2m
TAT1m
BAP2m
BAP3m
MEP1m
MEP2m
MEP3m
active proteinsGAP1ap
CAN1ap
PUT4ap
MUP3ap
DIP5ap
SAM3ap
AGP3ap
MUP1ap
HIP1ap
APL1ap
MMP1ap
AGP2ap
LYP1ap
AGP1ap
GNP1ap
TAT2ap
TAT1ap
BAP2ap
BAP3ap
MEP1ap
MEP2ap
MEP3ap
mRNA SSYm
GRR1m
GLN3m
GAT1m
active proteinsSSYap
GRR1ap
GLN3ap
GAT1ap
bibliography
1 A. G. Hinnebusch
2 B. Regenberg and L.D. Morten and C. Kielland-Brandt and S. Holmberg
3 H. Forsberg and P.O. Ljungdahl
4 B. Magasanik and C. A. Kaiser
5 J. Hofman-Bang
6 G. Giaever et al.
7 L. A. Urrestarazu, C. W. Borell and J. K. Bhattacharjee
15 Hinnebusch AG, Natarajan K.
16 Cigan AM, Bushman JL, Boal TR, Hinnebusch AG.
10 O. Grundman, H.U. Mosch and H. Braus
11 A. Feller, F. Ramos, A. Pierard and E. Dubois
12 A. Feller and F. Ramos and A. Pierard and E. Dubois
13 J. J. Tate and K. H. Cox and R. Rai and T. G. Cooper
14 F. Ramos and E. Dubois and A. Pierard
Description
amino acids
external ammonia
internal amino acids. Each amino acid has certain permeases
(aa_permeases) detailed below.
internal ammonia
metabolite in lysine biosynthesis pathway.
In general, the functions follow these rules:
If there is flow into it, but no flow out, the metabolite is absent (0).
If there is flow in and out, we set its value to 1.
If there is no flow into it. The metabolite is accumulate (2)
protein kinase
amino acids biosynthetic enzymes transcription regulator
lysine biosynthetic enzymes transcription regulator
negative regulator of CIT2 gene expression needed for alphaKetoglutarate synthesis
subunits of the translation initiation complex eIF3
hesis pathway enzymes
lysine biosynthetic enzymes
*replacing LYS7, see ref 6.C170
permease of Asp,Lys,Gly,Ala,Asn,Arg,Ser,Cys,his,Thr,Trp,Phe,Val,Met,Leu,Ile,Tyr
permease of Arg
permease of Ala,Val,Pro
permease of Met
permease of Asp,Glu,Gln,Asn,Ser
permease of Met
permease of Asp,Glu,Ser
permease of Met
permease of His
permease of Arg
permease of Met
permease of Leu.Thr
permease of Lys
permease of Ala,Gly,Val,Ile,Leu,Phe.Met.Cys,Gln,Asn,Ser,Thr,Tyr
permease of Leu,Met,Cys,Glu,Gln,Asn,Ser,Thr
permease of Ala,Gly,Phe,Trp,Tyr
permease of Val,Trp,Thr,Tyr
permease of Leu,Ile,Val,Ala,Phe,Trp,Met,Cys,Tyr
permease of Leu,Ile,Val,Ala,Phe,Trp,Met,Cys,Tyr,Thr
permease of ammonia
permease of ammonia
permease of ammonia
permease of Asp,Lys,Gly,Ala,Asn,Arg,Ser,Cys,his,Thr,Trp,Phe,Val,Met,Leu,Ile,Tyr
permease of Arg
permease of Ala,Val,Pro
permease of Met
permease of Asp,Glu,Gln,Asn,Ser
permease of Met
permease of Asp,Glu,Ser
permease of Met
permease of His
permease of Arg
permease of Met
permease of Leu.Thr
permease of Lys
permease of Ala,Gly,Val,Ile,Leu,Phe.Met.Cys,Gln,Asn,Ser,Thr,Tyr
permease of Leu,Met,Cys,Glu,Gln,Asn,Ser,Thr
permease of Ala,Gly,Phe,Trp,Tyr
permease of Val,Trp,Thr,Tyr
permease of Leu,Ile,Val,Ala,Phe,Trp,Met,Cys,Tyr
permease of Leu,Ile,Val,Ala,Phe,Trp,Met,Cys,Tyr,Thr
permease of ammonia
permease of ammonia
permease of ammonia
nutrient sensing system
Nitrogen catabolite repression regulator
Nitrogen catabolite repression regulator
The molecular and cellular biology of the yeast Saccaromyces: Gene expression (volume 2). Eds:
Substrate specificity and gene expression of the amino acid permeases in S. cerevisiae
Sensors of extracellular nutrients in S. cerevisiae
Nitrogen regulation in S. cerevisiae
Nitrogen catabolite repression in S. cerevisiae
Functional profiling of the S. cerevisiae genome
General and specific controls of lysine biosynthesis in S. cerevisiae
Gcn4p, a master regulator of gene expression, is controlled at multiple levels by diverse signals of starvation and stress.
A protein complex of translational regulators of GCN4 mRNA is the guanine nucleotide-exchange factor for translation initiation fact
Repression of GCN4 Translation by nitrogen starvation in S. Cerevisiae
In S. cerevisiae, feedback inhibition of homocitrate synthase by lysine modulate the activation of LYS gene expression by lysine
LYS80p of S. cerevisiae, previousely proposed as a specific repressor of LYS genes, is a pleiotropic regulatory factor identical to M
MKS1p is required for negative regulation of retrograde gene expression in S. cerevisiae but does not affect nitrogen catabolite repr
Control of enzyme synthesis in the lysine biosynthetic pathway of S. cerevisiae
Funtion Reference
-
-
Let aa_permease be the list of permeases of the amino acid.
Let Eaa be the external value of the amino acid.
Set aa_biosynthesis: if (INH3 >0) {aa_biosynthesis =1} -
else {aa_biosynthesis =0}.
if (max(aa_permeases) == 0) {retrun aa_biosynthesis}
else {return Eaa}
if (max(MEP1ap,MEP2ap,MEP3ap3) == 0) {return 0} -
else {return ENH3}
if (MKS1ap >=1) {return 0}
else if (min(LYS20,LYS21) ==0) {return 2} 1,12,13
else {return 1}
if (max(LYS20ap,LYS21ap)==0 OR IAlphaKetoGlutarate == 0) {return 0}
else: if(min(YJL200Cap,LYS2ap,LYS12ap,LYS4ap)==0) {return 2} 1
else {return 1}
if (min(YJL200Cap,LYS2ap,LYS1ap,LYS4ap) OR IHomoCytrate == 0) {return 0}
else: if(min(LYS9ap,LYS1ap)==0) {return 2} 1
else {return 1}
Set TranLys: if(LYP1ap==0) {TranLys=0} else {TranLys:=Elys}.
if (min(LYS9ap,LYS1ap)==0 OR IAlphaASAA == 0) {return TranLys} 1
else {return max(1, TranLys)}
1 -
1 -
1 -
1 -
Let min_Iaa=minimum value of all internal amino acids.
if (min(GCN2m,GCN1ap,GCN20ap) >=1) {return (2 - min_Iaa)} 8,9
else {return 0}
if (min(eIF3 subunits) == 0) {return 0}
else: if (INH3 == 0) {return GCN2ap - 1} 10,8,9
else {return GCN2ap}
if (LYS14m == 0) {return 0}
else: if (ASAA == 0} {return 1} 14
else: {return 2}
if(MKS1m == 0) {return 0} 12,13
else {return (2-INH3)}
1
1
1
1
1 9
1
1
1
1
1
equal to GCN3m
equal to GCD1m
equal to GCD6m
equal to GCD7m
equal to GCD2m
equal to GCD11m
equal to SUI2m
equal to SUI3m
equal to GCN20m
equal to GCN1m
LYS14ap+GCN4ap 14,7,1
1 1
1 1
1 1
LYS14ap+GCN4ap 14,7
1 1
LYS14ap+GCN4ap 14,7
LYS14ap+GCN4ap 14,7
1 1
equal to LYS1m 1
if(LYS5ap == 0) {return 0}
else {return LYS2m} 1
equal to LYS4m -
equal to LYS5m -
equal to LYS9m -
equal to LYS12m -
if (Ilys == 2) {return 0}
else {return LYS20m} 11
if (Ilys == 2) {return 0}
else {return LYS21m}
equal to YJL200Cm -
min(GLN3ap,GAT1ap) [NCR*]
2,4,5
1
1
1
1
1 2
1
1
1
1
1
Let min_Iaa=minimum value of all internal amino acids.
min(SSY1ap, GRR1ap,min_aa)
2,3
1
1 2
1
equal to GAP1m
equal to CAN1m
equal to PUT4m
equal to MUP3m
equal to DIP5m
equal to SAM3m
equal to AGP3m
equal to MUP1m
equal to HIP1m
equal to APL1m
equal to MMP1m 2
equal to AGP2m
equal to LYP1m
equal to AGP1m
equal to GNP1m
equal to TAT2m
equal to TAT1m
equal to BAP2m
equal to BAP3m
equal to MEP1m
equal to MEP2m
equal to MEP3m
1
1
1 3
1
equal to SSYm
equal to GRR1m
if(GLN3m==0){return 0}
else {return (2-min(IGln,Iglu))} 4,5
if(GAT1m==0){return 0}
else {return (2-min(IGln,Iglu))}
cold spring harbour laboratory press, Cold Spring Harbo
Curr. Genet 36: 317-328 (1999(
Curr genet 40:91-109 (2001)
gene 290: 1-18 (2002)
Molecular Biotechnology 12:35-73 (1999)
Nature 418: 387-391 (2002)
Curr. Genet. 9:341-344 (1985)
gnals of starvation and stress. Eukaryot Cell. 2002 Feb;1(1):22-32.
change factor for translation initiation factor 2 in yeast. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5350-4.
The journal of biological chemistry 276:25661-25671 (2
tion of LYS gene expression by lysine Eur. J. Biochem 261:163-170 (1999)
pleiotropic regulatory factor identical to Mks1p Yeast 13: 1337-1346 (1997)
but does not affect nitrogen catabolite repression-sensitive gene expression. The journal of biological chemistry 277:20477-20482 (2
Eur. J. Biochem 171: 171-176 (1988)
comments on function
determined by the medium
determined by the medium
amino acid may be transported
by its permease into the
cell, and biosynthesized.
NH3 enters the cell through
its permeases
MKS1down regulate CIT2 needed
to synthesis of IAlphaKetoGlutarate
Lysine is transported by its
permease (LYP1), and
biosynthesized.
INh3 effect MKS1 activity
General constrol of GCN4 and
lysine pathway-specific control
of LYS14.
feedback inhibition of homocitrate
synthase by lysine modulate
the activation
a simplification of
Nitrogen catabolite repression
a great simplification of the
nutrient sensing system
Nitrogen catabolite repression
triggered by presence of Glu and Gln
cold spring harbour laboratory press, Cold Spring Harbor, New-York, 1992.
Curr. Genet 36: 317-328 (1999(
Curr genet 40:91-109 (2001)
gene 290: 1-18 (2002)
Molecular Biotechnology 12:35-73 (1999)
Nature 418: 387-391 (2002)
Curr. Genet. 9:341-344 (1985)
Eukaryot Cell. 2002 Feb;1(1):22-32.
Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5350-4.
The journal of biological chemistry 276:25661-25671 (2001)
Eur. J. Biochem 261:163-170 (1999)
Yeast 13: 1337-1346 (1997)
The journal of biological chemistry 277:20477-20482 (2002)
Eur. J. Biochem 171: 171-176 (1988)
Variable Type Variable name Description
External conditions EOC External Osmotic Conditions
HOG pathway - Sln1 branch(negative regulator)
mRNA SLN1m
YPD1m
SSK1m
SSK2m
SSK22m
active protein SLN1ap * Osmosensor.
YPD1ap Histidine kinase. Negative regulator.
SSK1ap Aspartyl kinase
SSK2ap MAPKKK
SSK22ap MAPKKK - analogous to SSK2
HOG pathway - Sho1 branch (positive regulator)
mRNA SHO1m
CDC42m
CDC24m
STE20m
CLA4m
STE50m
STE11m
active Protein SHO1ap 4 transmembrane domains, SH3 domain.
Probably not an osmosensor by itself
CDC42ap Rho-like G-Protein. Binds Ste20 and Cla4
CDC24ap Exchange factor for Cdc42
STE20ap Kinase
CLA4ap similar function to Ste20
STE50ap Regulator.
Constitutively bound to Ste11 (ref. 13)
STE11ap MAPKKK
HOG pathway - general
mRNA PBS2m
HOG1m
PTP2m
PTP3m
PTC1m
PTC2m
PTC3m
active Protein PBS2ap MAPKK
Scaffold (in Sho1 branch)
cytHOG1ap MAPK
* Hog1 in Cytoplasm
* Active Hog1 is phosphorilated in both Tyr and
Thr residues
nuHOG1ap Hog1 in Nucleus
PTP2ap Tyrosine phosphatase
PTP3ap Tyrosine phosphatase
PTC1ap Serine/Threonine phosphatase
PTC2ap Serine/Threonine phosphatase
PTC3ap Serine/Threonine phosphatase
Hog1 translocation
mRNA GSP1m
NMD5m
active Protein GSP1ap
NMD5ap
TFs
Hot1m
Msn1m
Msn2m
Msn4m
active Protein Hot1ap * Recruits Hog1 to target promoters.
Most likely binds Hog1 in the nucleus.
* Has a physical interaction with Hog1
* Phos. upon osmotic sress - mainly by Hog1.
* Phosphorilation may be required for activity
Msn1ap Nuclear. Binding site similar to Hot1.
Most likely binds Hog1 in the nucleus
Does not need to be phosphorilated to be active.
Msn2ap Cyt+Nuc. Activator. Recognizes STRE.
Most likely binds Hog1 in the nucleus
Activated (phosphorilated) by PKA / Hog1
Msn4ap Cyt+Nuc. Activator. Recognizes STRE.
Most likely binds Hog1 in the nucleus
Activated (phosphorilated) by PKA / Hog1
PKA
mRNA PKA1m
PKA2m
PKA3m
active Protein PKAap
Osmotic-stress induced
mRNA GPD1m G3P dehydrogenase
GPP1m
GPP2m G3 phosphatase
GLO1m
DAK1m
TPK1m PKA1 (see above)
active Protein GPD1ap NAD1-dependent sn-glycerol 3-phosphate dehydrogenase
GPP1ap
GPP2ap
GLO1ap
DAK1ap
TPK1ap
Glycerol export channel
Fps1 * Glycerol transporter
* not part of the HOG pathway!
bibliography
1 S. Hohmann Osmotic Stress Signaling and Osmoadaptation in Yeasts
2 Unique and Redundant Roles for HOG MAPK Pathway Components as Revealed by W
S.M.O'Rourke and I. Herskowitz
3 Yeast go the whole HOG for the
S.M.O'Rourke, I. Herskowitz and E.K. O'Shea hyperosmotic response
4 The Transcriptional Response of Saccharomyces cerevisiae to Osmotic Shock
M. Rep, M. Krantz, J. M. Thevelein and S. Hohmann
5 A Third Osmosensing Branch in S.C. Requires the Msb2 protein and Functions in parall
S.M.O'Rourke and I. Herskowitz
6 Two protein-tyrosine phosphatases C, Ota I.
Jacoby T, Flanagan H, Faykin A, Seto AG, Mattisoninactivate the osmotic stress response pathway in ye
7 Ptc1, a type 2C Amin D, Ota I.
Warmka J, Hanneman J, Lee J,Ser/Thr phosphatase, inactivates the HOG pathway by dephosphorylatin
8 HOG on
Srikumar P. Chellappan the Promoter: Regulation of the Osmotic Stress Response
9 Regulation of the Saccharomyces
Wurgler-Murphy SM, Maeda T, Witten EA, Saito Hcerevisiae HOG1 mitogen-activated protein kinase by
10 Osmostress-induced transcription by Hot1
Alepuz PM, de Nadal E, Zapater M, Ammerer G, Posas F. depends on a Hog1-mediated recruitment of
11 A signaling mucin at the head of the Cdc42- and MAPK-dependent filamentous growth p
Cullen PJ, Sabbagh W Jr, Graham E, Irick MM, van Olden EK, Neal C, Delrow J, Bardwell L, Sprague G
12 Protein-protein interaction BJ, Davidson crucial role in controlling the sho1p-mediated s
Marles JA, Dahesh S, Haynes J, Andrews affinity plays aAR
13 Functional Characterization of the Interaction of Ste50p with Ste11p MAPKKK in Saccha
Cunle Wu, Ekkehard Leberer, David Y. Thomas, and Malcolm Whiteway
14 F, Saito H
Raitt DC, PosasYeast Cdc42 GTPase and Ste20 PAK-like kinase regulate Sho1-dependent activation o
15 MAP KinaseAlbertyn, Matthew Alexander, and Kenneth Davenport
Michael C. Gustin, Jacobus Pathways in the Yeast Saccharomyces cerevisiae
Funtion Reference
0 - normal, 1 - moderate stress, 2 - high stress
1
1
1
1
1
Sln1m AND (2 - EOC) 1
Ypd1m AND Sln1ap
Ssk1m AND Ypd1ap
9
Ssk2m AND Ssk1ap 1
Ssk22m AND Ssk1ap 1
1
1
1
1
1
1
1
Sln1m AND EOC
1
Cdc42m AND Cdc24 AND Sho1ap AND Pbs2ap?
CDC24m
Ste20m AND Cdc42ap 1
Cla4m AND Cdc42ap
Ste50m
13
Ste11m AND (Ste20ap OR Cla4ap) AND Ste50ap
1
1
max (1, nuHOG1ap) 5
6
max (1, nuHOG1ap) 6
1
1
1
Ssk2ap OR Ssk22ap OR 3
(Sho1ap AND Ste11ap)
7
1
Pbs2ap AND (NOT 3
(PTP2ap OR PTC1ap)) 1
1
6,7
(cytHOG1ap AND GSP1ap AND 1
NMD5ap) AND
(NOT (PTP2ap OR PTC1ap))
q 1
6,7
PTP2m 6
PTP3m 6
PTC1m 7
PTC2m 7
PTC3m 7
1
1
1 1
1 1
1
1
1
1
Hot1m AND Hog1ap 1
8
Msn1m 1
10
Msn2m AND (PKAap OR Hog1ap) 1
8
Msn4m AND (PKAap OR Hog1ap) 1
8
max(1, Hog1ap) 4
1
1
PKA1m AND PKA2m AND PKA3m
Hog1ap AND Hot1ap AND Msn1ap 4,8
8
1
Hog1ap AND Hot1ap 4
Hog1 AND (Msn2 OR Msn4) 4
Hog1 AND (Msn2 OR Msn4) 4
max(1, Hog1ap) 4
GPD1m
GPP1m
GPP2m
GLO1m
DAK1m
TPK1m
opposite of EOC 15
ptation in Yeasts
MAPK Pathway Components as Revealed by Whole-Genome Expression Analysis
motic response
aromyces cerevisiae to Osmotic Shock
quires the Msb2 protein and Functions in parallel with the Sho1 branch
ivate the osmotic stress response pathway in yeast by targeting the mitogen-activated protein kinase, Hog1.
activates the HOG pathway by dephosphorylating the mitogen-activated protein kinase Hog1.
Osmotic Stress Response
siae HOG1 mitogen-activated protein kinase by the PTP2 and PTP3 protein tyrosine phosphatases
1 depends on a Hog1-mediated recruitment of the RNA Pol II
42- and MAPK-dependent filamentous growth pathway in yeast
crucial role in controlling the sho1p-mediated signal transduction pathway in yeast
ction of Ste50p with Ste11p MAPKKK in Saccharomyces cerevisiae
e kinase regulate Sho1-dependent activation of the Hog1 MAPK pathway
haromyces cerevisiae
comments on function
Sln1 - Ypd1 - Ssk1
(phosphorelay system)
Histidine Kinase is activated by hypo-
osmolarity (cell swelling) and inhibited by
hyper-osmolarity (cell shrinking).
* Auto-phosphorilates itself under low
osmolarity
phosphorilated on His by Sln1
phosphorilated on Asp (+ stabilized) by Ypd1
(Phosphorilated form is inactive)
Activated by de-phosphorilated
Ssk1 (val should be opposite of Ssk1ap)
Activation involves auto-phosphorilation
Activated by de-phosphorilated
Ssk1 (val should be opposite of Ssk1ap)
Activation involves auto-phosphorilation
* Activated by high external osmolarity.
* Activation may involve demasking of SH3 domain
Activated by Sho1-Pbs2 complex (how?)
localization to the
cell surface + activation requires Cdc42
Didn't find evidence of change in activation/expression due to hyperosmitic conditions
In fact evidence shows it is constitutively bound to Ste11
Activated (phos.) by Ste20 (or Cla4). Regulated by Ste50
* Supposedly induced - didn't find evidence
* Induction may involve Msn2/4 as well as
other elements.
Transcription may be regulated by HOG pathway (how?)
Transcription may be regulated by HOG pathway (how?)
Transcription may be regulated by HOG pathway (how?)
* Phosphorilated and activated by MAPKKK
(Ssk2/22 or Ste11). Phos. On Ser and Thr.
* Supressed (de-phosphorilated and/or
blocked) by Ptc2/3
* In the Sho1 branch - recruited to the cell
surface by Sho1 binding in its SH3 domain (this is crucial)
* Phosphorilated and activated by MAPKK
Pbs2, may also be auto-phosphorilated
* Phos. On Thr and Tyr.
* Phosphorilated in the cytosol!
* Supressed (de-phosphorilated and/or
blocked) by Ptp2/(3) and Ptc1
* Activated (P) Hog1 is translocated into the nucleus
by Gsp1p and Nmd5p.
* Dephosphorylation and export from the nucleus are probably separated
* Supressed (de-phosphorilated and/or
blocked) by Ptp2/(3) and Ptc1
Expression induced by Hog1???
* Induced by Hog1, Hot1, Msn1
* Hot1 binds directly to promoter
* Increased binding upon osmotic stress
requires Hog1.
* Only phosphorilated Hog1 binds to promoter,
and binding requires Hot1.
Induced by Hog1, Hot1 (a lot less than the others)
Induced by Hog1, Hot1
Msn2/4 are redundant
Msn2/4 are redundant
inhibited by hyperosmotic stress in a manner
independent of the HOG pathway
-Genome Expression Analysis
ith the Sho1 branch
by targeting the mitogen-activated protein kinase, Hog1.
he mitogen-activated protein kinase Hog1.
PTP2 and PTP3 protein tyrosine phosphatases
al transduction pathway in yeast
myces cerevisiae
e Hog1 MAPK pathway