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Question
What is the phosphatase of PTEN?
What is the casein kinase activator or inhibitor?
What is the proteins which bind to PTEN?
Answer: p53, Casein kinase 2, and so on.
PTEN is dephospharylated by insulin-like growth factor and maybe activated.
SHIPとの関係は？
総説を読んで。
CSの共同体のCSの判断基準において、mental retardation はminor criteriaに入っている。ということは、それほどCSにおいて、mental retardationは重要なphenotypeではないらしい。これは、ちょっと残念。
結晶構造解析の結果から、C2ドメインとホスファターゼドメインはくっついている。
C2ドメインmutationも同様にCSで見られる。point mutation ではなくてnonsence mutation and deletion mutationである。おそらく、C2ドメインはPSなどにくっつくのではないかと推測されていて、膜に行くことができないために、CSになるのではないかと推測される。
ちなみに、ホスファターゼドメインはアルファへリックス。
C2ドメインはベータシートがメインだね。
PTENのタンパク質の安定性は、S380, 382,383のリン酸化による。
カゼインキナーゼが370, 380, 383, 385をリン酸化する。
366はGSK3bによってリン酸化される。
370, 380, 385はCK2によってリン酸化される。
Some author said that 380, 382, 383 and 385 is phosphorylation site.
383 is dephosphorylated by PTEN itself and regulates migration activity(science 2003).
*1. History of PTEN
&bold(){}
PTEN is the acronym of phosphatase and tensin homologue on chromosome 10.
PTEN was cloned from three groups in 1997 as a tumor suppressor for gliomas.
[[rat PTEN>http://www.ncbi.nlm.nih.gov/nuccore/NM_031606.1]]
[[homo sapiens PTEN>http://www.ncbi.nlm.nih.gov/nuccore/110224474?report=genbank]]
*2. What is PTEN gonna cause?
&bold(){}
PTEN germline mutations are associated with Cowden disease, Bannayan-Zonana syndrome and Lhermitte Duclos disease which gives disorganized hamartomas in various organs.
Cowden syndrome patients exist 1/200,000.
Mutation of PTEN is a common event in diverse human cancers, occuring in about 50% of glioblastoma, endometrial, prostate carcinoma.Germline mutations in PTEN are associated with the dominantly inherited Cowden syndromes.
Cowden syndrome is firstly described in 1963.
CS is qutosomal dominant disorder.
It was reported that the gene for this disease is in 10q22-q23 using linkage analysis of 12 families in 1996.
Main features are macrocephaly and mental retardation.
Approximately 80% of CS patients have PTEN mutations.
[[cowden disease syndrome>http://www.ncbi.nlm.nih.gov/omim/158350]]
[[cowden2>http://emedicine.medscape.com/article/1093383-overview]]
PTEN null mice exhibit embryonic lethality.
There are a bunch of conditional PTEN KO mice including astrocyte KO mice using GFAP-Cre and dividing neuronal cells KO mice using Nse-Cre.
First paper shows LTP reduction and macrocephaly.
Second paper indicates that this KO mice exhibit abnormal social interaction like autism and macrocephaly.
*&bold(){3. What is gonna happen when this protein is removed?}
PTEN KO mice show macrocephaly in organ and cell level as common feature.
Morgan Sheng shows that knockdown of PTEN in CA1 pyramidal neuronal cells in hippocampus increases dendrite branching.
*&bold(){4. Molecular mechanism of PTEN}
The molecular weight of PTEN is 120kDa.
The length of amino acids is 403.
Domain structure
PTEN's crystal structure has been decided.
[[crystal structure of PTEN>http://www.ncbi.nlm.nih.gov/sites/entrez]]
#image(domain structure.BMP,width=400,height=300,title=PTEN)
Starting from N-terminus, PTEN has catalytic domain, C2 domain and PDZ domain.
In addition, PIP2 binding domain is there in N terminus.
PTEN also has two PEST domain, which is important for PTEN stability.
[[PTEN-PEST domain>http://www.ncbi.nlm.nih.gov/pubmed/11156408]]
PTEN was initially believed to be a dual specificity phospho-tyrosine phosphatase (PTP).
PTEN phosphorylates denature focal adhesion kinase (FAK) in vitro, and overexpression of PTEN in mammalian cells decreases FAK phosphorylation.
In addition Shc has also been proposed as a substrate of PTEN.
However PTEN is strikingly poor catalyst toward most artificial PTP substrates. PTEN prefers negatively charged substrates such as PIP3.
In addition, it is reported that several frequently occurring missense mutations in Cowden disease (G129E) and in glioblastoma (R15S and R15I)result in a loss of lipid-specific phosphatase activity, whereas PTP activity is largely unaffected.
In 2004, there was the paper in which PTEN downregulation causes decrease in expression level of NMDAR1 and NMDAR2B but not NMDAR2A.
PTEN directly binds to NR1 and indirectly binds to NR2B.
They found out LTP decrease is caused by PTEN RNAi through NR downregulation.
Furthermore, they used C124A and G129E mutation of PTEN.
C124A is deficient in phosphatase and PIP3 phosphatase activity.
C129E is deficient in only PIP3 phosphatase activity.
They found out G129E mutation increases LTP, but C124A decrease LTP with electrophysiology.
Taken together, it seems that now PIP3 is preferential substrate for PTEN.
Basically C2 domain is involved in Ca++-mediated membrane binding.
However the C2 domain of PTEN is in a Ca++ independent manner.
From this aspect, PTEN C2 domain is similar with one of novel PKC.
PTEN C2 domain is known to bind to phospholipid, like PS.
This indicates that mutations in C2 domain of PTEN, which leads to Cowden syndrome, causes deficient in PTEN binding to the plasma membrane, resulting in PIP3 increase.
PDZ domain ligand gives binding with a bunch of proteins including NMDA receptor, SAP97 and Bazooka directly.
About confomational change of PTEN
1. PIP2 binding.
some papers shows that PIP2 activates the phosphatase domain via a conformational change.
2. phosphorylation
3. C2 domain
4. binding to other proteins
*&bold(){5. Localization of PTEN}
PTEN is expressed in cytosol and nuclear.
One paper shows that GSK3beta and casein kinase lead to phosphorylation of PTEN, which leads to recruit PTEN and Myosin V complex to plasma membrane, resulting in PTEN activation.
*&bold(){6. post-translational modification}
It is reported that casein kinase phosphorylates PTEN, which leads to PTEN activation.
ubiquitination
oxidation
*&bold(){7. what is the effecter of PTEN?}
FAK and Shc as well as PIP3 have been reported.
*&bold(){8. what is the regulator of PTEN?}
It is known that GSK3beta and casein kinase regulate PTEN activity.
How to answer for question as follows.
It is known that protein tyrosine phosphatase is involved in tumore supressor.
However, there is no example of PTPase that function as tumour suppressors.
1997, two groups reported PTEN is plausible candidate, which is located in 10p23.
PTEN is mutated and deleted in a wide variety of tumours and tumours cell lines.
Also germline transmission of mutations in PTEN were observed in Cowden disease.
PTEN is dual phosphatase, which substrates is proteins and PIP3.
However, PIP3 regulates Akt, which is related to tumour and survival signaling.
So, PTEN's main role concerning to tumour suppressor is most likely PIP3 dephosphorylation.
At least, it is reported that PTEN regulates Akt kinase activity in hippocampal neuron and increase
sensitivity of apoptosis.
You said that PIP3 is produced by mGluR pathway.
However, restrict to glutamate uncaging, mGluR pathway seems not to relate to structual plasticity. So How is PIP3 produced?
Answer: Exactly one paper shows that mGluR is not related to structual plasticity using MCPG. However there are several pathway that regulates PIP3 dynamics. About PI3K, Ras binds to PI3K directly and regulates activity of PI3K. About PTEN, CK2 and GSK3b regulate PTEN activity, leading to reducing PIP3. So, PIP3 increase or decreases occurs using these pathway. I think.
why PTEN causes something wrong?
Because PI3K has a lot of splicing varients and homologue.
However PTEN doesn't have.
That is why PTEN cause some wrong..
How is PTEN activated?
It remains unknow. One paper says that casein kinase phosphorylates PTEN and PTEN MyosinV complex moves to plasma membrane. casein kinase inhibitor is comercially available.
I can examine whether PIP3 decrease abolished by casein kinase inhbitor.
About SHIP
SHIP is abbrebiation of SH2 domain-containing inositol
polyphosphate 5-phosphatase.
Findings so far published concerning the functional
significance of SHIP are largely confined to the hemopoietic
system.
In brain, SHIP2 is not significantly expressed in hippocampus.
[[SHIP2>http://www.ncbi.nlm.nih.gov/pubmed/10648902]]
And SHIP reduces the amount of PIP3 and Akt activity in glioblastoma cells.
[[SHIP>http://www.ncbi.nlm.nih.gov/pubmed/10958682]]
Question
What is the phosphatase of PTEN?
What is the casein kinase activator or inhibitor?
What is the proteins which bind to PTEN?
Answer: p53, Casein kinase 2, and so on.
PTEN is dephospharylated by insulin-like growth factor and maybe activated.
SHIPとの関係は？
総説を読んで。
CSの共同体のCSの判断基準において、mental retardation はminor criteriaに入っている。ということは、それほどCSにおいて、mental retardationは重要なphenotypeではないらしい。これは、ちょっと残念。
結晶構造解析の結果から、C2ドメインとホスファターゼドメインはくっついている。
C2ドメインmutationも同様にCSで見られる。point mutation ではなくてnonsence mutation and deletion mutationである。おそらく、C2ドメインはPSなどにくっつくのではないかと推測されていて、膜に行くことができないために、CSになるのではないかと推測される。
ちなみに、ホスファターゼドメインはアルファへリックス。
C2ドメインはベータシートがメインだね。
PTENのタンパク質の安定性は、S380, 382,383のリン酸化による。
カゼインキナーゼが370, 380, 383, 385をリン酸化する。
366はGSK3bによってリン酸化される。
370, 380, 385はCK2によってリン酸化される。
Some author said that 380, 382, 383 and 385 is phosphorylation site.
383 is dephosphorylated by PTEN itself and regulates migration activity(science 2003).
*1. History of PTEN
&bold(){}
PTEN is the acronym of phosphatase and tensin homologue on chromosome 10.
PTEN was cloned from three groups in 1997 as a tumor suppressor for gliomas.
[[rat PTEN>http://www.ncbi.nlm.nih.gov/nuccore/NM_031606.1]]
[[homo sapiens PTEN>http://www.ncbi.nlm.nih.gov/nuccore/110224474?report=genbank]]
*2. What is PTEN gonna cause?
&bold(){}
PTEN germline mutations are associated with Cowden disease, Bannayan-Zonana syndrome and Lhermitte Duclos disease which gives disorganized hamartomas in various organs.
Cowden syndrome patients exist 1/200,000.
Mutation of PTEN is a common event in diverse human cancers, occuring in about 50% of glioblastoma, endometrial, prostate carcinoma.Germline mutations in PTEN are associated with the dominantly inherited Cowden syndromes.
Cowden syndrome is firstly described in 1963.
CS is qutosomal dominant disorder.
It was reported that the gene for this disease is in 10q22-q23 using linkage analysis of 12 families in 1996.
Main features are macrocephaly and mental retardation.
Approximately 80% of CS patients have PTEN mutations.
[[cowden disease syndrome>http://www.ncbi.nlm.nih.gov/omim/158350]]
[[cowden2>http://emedicine.medscape.com/article/1093383-overview]]
PTEN null mice exhibit embryonic lethality.
There are a bunch of conditional PTEN KO mice including astrocyte KO mice using GFAP-Cre and dividing neuronal cells KO mice using Nse-Cre.
First paper shows LTP reduction and macrocephaly.
Second paper indicates that this KO mice exhibit abnormal social interaction like autism and macrocephaly.
*&bold(){3. What is gonna happen when this protein is removed?}
PTEN KO mice show macrocephaly in organ and cell level as common feature.
Morgan Sheng shows that knockdown of PTEN in CA1 pyramidal neuronal cells in hippocampus increases dendrite branching.
*&bold(){4. Molecular mechanism of PTEN}
The molecular weight of PTEN is 47kDa.
The length of amino acids is 403.
Domain structure
PTEN's crystal structure has been decided.
[[crystal structure of PTEN>http://www.ncbi.nlm.nih.gov/sites/entrez]]
#image(domain structure.BMP,width=400,height=300,title=PTEN)
Starting from N-terminus, PTEN has catalytic domain, C2 domain and PDZ domain.
In addition, PIP2 binding domain is there in N terminus.
PTEN also has two PEST domain, which is important for PTEN stability.
[[PTEN-PEST domain>http://www.ncbi.nlm.nih.gov/pubmed/11156408]]
PTEN was initially believed to be a dual specificity phospho-tyrosine phosphatase (PTP).
PTEN phosphorylates denature focal adhesion kinase (FAK) in vitro, and overexpression of PTEN in mammalian cells decreases FAK phosphorylation.
In addition Shc has also been proposed as a substrate of PTEN.
However PTEN is strikingly poor catalyst toward most artificial PTP substrates. PTEN prefers negatively charged substrates such as PIP3.
In addition, it is reported that several frequently occurring missense mutations in Cowden disease (G129E) and in glioblastoma (R15S and R15I)result in a loss of lipid-specific phosphatase activity, whereas PTP activity is largely unaffected.
In 2004, there was the paper in which PTEN downregulation causes decrease in expression level of NMDAR1 and NMDAR2B but not NMDAR2A.
PTEN directly binds to NR1 and indirectly binds to NR2B.
They found out LTP decrease is caused by PTEN RNAi through NR downregulation.
Furthermore, they used C124A and G129E mutation of PTEN.
C124A is deficient in phosphatase and PIP3 phosphatase activity.
C129E is deficient in only PIP3 phosphatase activity.
They found out G129E mutation increases LTP, but C124A decrease LTP with electrophysiology.
Taken together, it seems that now PIP3 is preferential substrate for PTEN.
Basically C2 domain is involved in Ca++-mediated membrane binding.
However the C2 domain of PTEN is in a Ca++ independent manner.
From this aspect, PTEN C2 domain is similar with one of novel PKC.
PTEN C2 domain is known to bind to phospholipid, like PS.
This indicates that mutations in C2 domain of PTEN, which leads to Cowden syndrome, causes deficient in PTEN binding to the plasma membrane, resulting in PIP3 increase.
PDZ domain ligand gives binding with a bunch of proteins including NMDA receptor, SAP97 and Bazooka directly.
About confomational change of PTEN
1. PIP2 binding.
some papers shows that PIP2 activates the phosphatase domain via a conformational change.
2. phosphorylation
3. C2 domain
4. binding to other proteins
*&bold(){5. Localization of PTEN}
PTEN is expressed in cytosol and nuclear.
One paper shows that GSK3beta and casein kinase lead to phosphorylation of PTEN, which leads to recruit PTEN and Myosin V complex to plasma membrane, resulting in PTEN activation.
*&bold(){6. post-translational modification}
It is reported that casein kinase phosphorylates PTEN, which leads to PTEN activation.
ubiquitination
oxidation
*&bold(){7. what is the effecter of PTEN?}
FAK and Shc as well as PIP3 have been reported.
*&bold(){8. what is the regulator of PTEN?}
It is known that GSK3beta and casein kinase regulate PTEN activity.
How to answer for question as follows.
It is known that protein tyrosine phosphatase is involved in tumore supressor.
However, there is no example of PTPase that function as tumour suppressors.
1997, two groups reported PTEN is plausible candidate, which is located in 10p23.
PTEN is mutated and deleted in a wide variety of tumours and tumours cell lines.
Also germline transmission of mutations in PTEN were observed in Cowden disease.
PTEN is dual phosphatase, which substrates is proteins and PIP3.
However, PIP3 regulates Akt, which is related to tumour and survival signaling.
So, PTEN's main role concerning to tumour suppressor is most likely PIP3 dephosphorylation.
At least, it is reported that PTEN regulates Akt kinase activity in hippocampal neuron and increase
sensitivity of apoptosis.
You said that PIP3 is produced by mGluR pathway.
However, restrict to glutamate uncaging, mGluR pathway seems not to relate to structual plasticity. So How is PIP3 produced?
Answer: Exactly one paper shows that mGluR is not related to structual plasticity using MCPG. However there are several pathway that regulates PIP3 dynamics. About PI3K, Ras binds to PI3K directly and regulates activity of PI3K. About PTEN, CK2 and GSK3b regulate PTEN activity, leading to reducing PIP3. So, PIP3 increase or decreases occurs using these pathway. I think.
why PTEN causes something wrong?
Because PI3K has a lot of splicing varients and homologue.
However PTEN doesn't have.
That is why PTEN cause some wrong..
How is PTEN activated?
It remains unknow. One paper says that casein kinase phosphorylates PTEN and PTEN MyosinV complex moves to plasma membrane. casein kinase inhibitor is comercially available.
I can examine whether PIP3 decrease abolished by casein kinase inhbitor.
About SHIP
SHIP is abbrebiation of SH2 domain-containing inositol
polyphosphate 5-phosphatase.
Findings so far published concerning the functional
significance of SHIP are largely confined to the hemopoietic
system.
In brain, SHIP2 is not significantly expressed in hippocampus.
[[SHIP2>http://www.ncbi.nlm.nih.gov/pubmed/10648902]]
And SHIP reduces the amount of PIP3 and Akt activity in glioblastoma cells.
[[SHIP>http://www.ncbi.nlm.nih.gov/pubmed/10958682]]
