loading...| Preferred Name |
Cowden Syndrome |
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| Synonyms |
PathwayType: signaling Description: Cowden syndrome (CS) is a rare autosomal dominant hereditary disorder. Pathway is built manually using published studies. CellType: epithelial cell Tissue: epithelium Organ: thyroid gland Organ_System: reproductive system Organ: intestine CellType: mammary epithelial cell Organ_System: endocrine system PMID: 18781191 Notes: Headnote: Cowden syndrome (CS), also known as Cowden disease and multiple hamartoma syndrome, is a rare autosomal dominant hereditary disorder. CS is characterized by multiple hamartomas and an increased risk for developing neoplasms, particularly breast, endometrial, thyroid, kidney, and colorectal cancers. CS has been estimated to affect 1 in every 200,000 individuals. Approximately 80% of CS patients have germline mutations in the PTEN gene. Rare cases of CS are caused by germline mutations in SDHB/D, BMPR1A, PIK3CA, and AKT1 genes. Signaling description: Mutations in the PTEN gene cause the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling pathways. Specifically, PIK3CA activates AKT1 via PIP3 and PDPK1. Since PTEN protein dephosphorylates PIP3 and inhibits the AKT-mediated signaling, mutations in PTEN activate AKT1. Also, PTEN dephosphorylates SHC1, which regulates the ERK (MAPK1/3), and mutations in PTEN gene result in the activation of SHC1 and, consequently the ERK signaling. Outcome effects: The constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling pathways which leads to block of apoptosis, loss of differentiation, migration, and redundant proliferation of epithelial cells. Activated AKT1 phosphorylates and activates CREB1 and MTOR, while inhibiting TP53. CREB1 regulates the transcription of BCL2, whereas MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits GSK3B (glycogen synthase kinase 3 beta) leading to cytosolic CTNNB1 stabilization. Cytosolic CTNNB1 protein then translocates into the nucleus where it interacts with TCF7 (T-cell factor 7) and LEF1 (lymphoid enhancing factor 1) to induce the expression of downstream target genes that are involved in cell proliferation and differentiation. Activated AKT1 also inhibits FOXO1/FOXO3 (forkhead box O1/O3), MAP3K5, and JNK-cascade. In addition, AKT1 phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. PDPK1, via PRKCA induces SRC which regulates Janus kinases 1/2 (JAK1/2) involved in cell growth regulation. FurtherThe ERK (MAPK1/3) signaling pathway induces genes involved in cell proliferation. PTEN dephosphorylates PTK2 that binds BCAR1 involved in cell migration. Lastly, mutations in PTEN gene facilitate cell migration. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PMID: 23246288 NodeType: Pathway Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd651c77-1c77-4357-b506-191f2e130d9b PMID: 18678321 Organ_System: digestive system Organ: uterus Organ_System: integumentary system Organ: breast Organ_System: urinary tract Pathway_Author: M. Zharkova ORCID:0000-0001-8706-9411 Organ: kidney Source: Diseases |
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| ID |
urn:agi-pathway:uuid-fd651c77-1c77-4357-b506-191f2e130d9b |
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| database_cross_reference |
PS:PathwayType PS:Description PS:Tissue PS:Pathway_Author PS:Link PS:CellType PS:Organ_System PS:PMID PS:NodeType PS:Notes PS:Organ PS:Source |
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| has_exact_synonym |
PathwayType: signaling Description: Cowden syndrome (CS) is a rare autosomal dominant hereditary disorder. Pathway is built manually using published studies. CellType: epithelial cell Tissue: epithelium Organ: thyroid gland Organ_System: reproductive system Organ: intestine CellType: mammary epithelial cell Organ_System: endocrine system PMID: 18781191 Notes: Headnote: Cowden syndrome (CS), also known as Cowden disease and multiple hamartoma syndrome, is a rare autosomal dominant hereditary disorder. CS is characterized by multiple hamartomas and an increased risk for developing neoplasms, particularly breast, endometrial, thyroid, kidney, and colorectal cancers. CS has been estimated to affect 1 in every 200,000 individuals. Approximately 80% of CS patients have germline mutations in the PTEN gene. Rare cases of CS are caused by germline mutations in SDHB/D, BMPR1A, PIK3CA, and AKT1 genes. Signaling description: Mutations in the PTEN gene cause the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling pathways. Specifically, PIK3CA activates AKT1 via PIP3 and PDPK1. Since PTEN protein dephosphorylates PIP3 and inhibits the AKT-mediated signaling, mutations in PTEN activate AKT1. Also, PTEN dephosphorylates SHC1, which regulates the ERK (MAPK1/3), and mutations in PTEN gene result in the activation of SHC1 and, consequently the ERK signaling. Outcome effects: The constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling pathways which leads to block of apoptosis, loss of differentiation, migration, and redundant proliferation of epithelial cells. Activated AKT1 phosphorylates and activates CREB1 and MTOR, while inhibiting TP53. CREB1 regulates the transcription of BCL2, whereas MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits GSK3B (glycogen synthase kinase 3 beta) leading to cytosolic CTNNB1 stabilization. Cytosolic CTNNB1 protein then translocates into the nucleus where it interacts with TCF7 (T-cell factor 7) and LEF1 (lymphoid enhancing factor 1) to induce the expression of downstream target genes that are involved in cell proliferation and differentiation. Activated AKT1 also inhibits FOXO1/FOXO3 (forkhead box O1/O3), MAP3K5, and JNK-cascade. In addition, AKT1 phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. PDPK1, via PRKCA induces SRC which regulates Janus kinases 1/2 (JAK1/2) involved in cell growth regulation. FurtherThe ERK (MAPK1/3) signaling pathway induces genes involved in cell proliferation. PTEN dephosphorylates PTK2 that binds BCAR1 involved in cell migration. Lastly, mutations in PTEN gene facilitate cell migration. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PMID: 23246288 NodeType: Pathway PMID: 18678321 Organ_System: digestive system Organ: uterus Organ_System: integumentary system Organ: breast Organ_System: urinary tract Pathway_Author: M. Zharkova ORCID:0000-0001-8706-9411 Organ: kidney Source: Diseases |
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| id |
urn:agi-pathway:uuid-fd651c77-1c77-4357-b506-191f2e130d9b |
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| label |
Cowden Syndrome |
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| notation |
uuid-fd651c77-1c77-4357-b506-191f2e130d9b |
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| prefLabel |
Cowden Syndrome |
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| treeView |
urn:agi-folder:c urn:agi-folder:endocrine_system urn:agi-folder:reproductive_system urn:agi-folder:urinary_tract urn:agi-folder:digestive_system urn:agi-folder:hereditary_syndromes_associated_with_breast_and/or_ovarian_cancer urn:agi-folder:epithelium urn:agi-folder:integumentary_system |
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| subClassOf |
urn:agi-folder:c urn:agi-folder:endocrine_system urn:agi-folder:reproductive_system urn:agi-folder:urinary_tract urn:agi-folder:digestive_system urn:agi-folder:hereditary_syndromes_associated_with_breast_and/or_ovarian_cancer urn:agi-folder:epithelium urn:agi-folder:integumentary_system |