PTEN Sensing Pathway

Curator(s): Peter D'Adamo

Phosphatase and tensin homolog (PTEN) is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers.PThe core phosphatidylinositol 3-kinase (PI3K) signalling pathway (indicated by blue symbols) begins with PI3K activation (indicated by pink symbol) by receptor tyrosine kinases (RTKs). PI3K activity phosphorylates and converts the lipid second messenger phosphatidylinositol (4,5) bisphosphate (PIP2) into phosphatidylinositol (3,4,5) triphosphate (PIP3), which recruits and activates phosphatidylinositol-dependent kinase 1 (PDK1). PDK1 in turn phosphorylates and activates protein kinase B (PKB, also known as AKT), which inhibits the activities of the forkhead (FOXO) transcription factors (which are mediators of apoptosis and cell-cycle arrest), resulting in cell proliferation and survival. The tumour-suppressor phosphatase with tensin homology (PTEN) negatively regulates PI3K signalling by dephosphorylating PIP3, converting it back to PIP2. The Ras signalling pathway (orange symbols) can be triggered by a set of RTKs that are activated by growth factors. Ras can activate PI3K both directly and indirectly. The activation status of p53 can also affect the outcome of PI3K signalling by interacting with the PKB-regulated FOXO transcription factors and with extracellular-regulated kinase 1 (ERK1) and ERK2. Other members of the PI3K signalling pathway include SGK (serum- and glucocorticoid-induced kinase), TSC1/TSC2 (tuberous sclerosis 1 and 2), RHEB (Ras homologue enriched in brain), TOR (target of rapamycin), 4EBP (eukaryotic initiation factor 4E (EIF4E)-binding protein), p70S6K (ribosomal protein, S6 kinase 70kD), and PP2A (protein phosphatase 2A). Members of the RTK–Ras signalling pathway include GRB2 (growth factor receptor-bound protein 2), SOS, Ras, Raf, MEK (mitogen-activated ERK kinase) and ERK — activation of this pathway leads to cell proliferation.[Nature Reviews]    

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PTEN Sensing Pathway cluster_Nucleus Nucleus cluster_node28 Cell Membrane node1 1 node2 1 Ras Ras->node2 Ras v-raf-1 murine leukemia viral oncogene homolog 1 RAF1 Ras->RAF1 PI3K Ras->PI3K SOS SOS->Ras p70S6K Protein Synthesis p70S6K->Protein Synthesis PP2A p53 PP2A->p53 node3 2 RAF1->node3 RAF1 node4 MEK1/2 RAF1->node4 node7 ERK1/2 node4->node7 node5 GRB2 CRK node5->SOS node5->PI3K node6 15 node8 2 phosphatase and tensin homolog PTEN PTEN->node8 PTEN SHC (Src homology 2 domain containing) transforming protein 1 SHC1 PTEN->SHC1 FAK PTEN->FAK node9 3 pyruvate dehydrogenase kinase,isozyme 1 PDK1 node12 PKB/AKT PDK1->node12 SGK PDK1->SGK node10 8 PI3K->node10 PI3K PIP3 PI3K->PIP3 node11 17 node12->node11 PKB/AKT node14 TSC2/TSC1 node12->node14 BCL2-associated agonist of cell death BAD node12->BAD p27 node12->p27 GSK3 node12->GSK3 forkhead box O1 FOXO1 node12->FOXO1 forkhead box O3 FOXO3 node12->FOXO3 forkhead box O4 FOXO4 node12->FOXO4 node13 1 node14->node13 TSC2/TSC1 Ras homolog enriched in brain RHEB node14->RHEB mechanistic target of rapamycin (serine/threonine kinase) MTOR RHEB->MTOR node15 20 MTOR->p70S6K MTOR->PP2A MTOR->node15 MTOR node16 4EBP MTOR->node16 eukaryotic translation initiation factor 4E EIF4E node16->EIF4E node17 1 EIF4E->node17 EIF4E EIF4E->Protein Synthesis Growth Factor GFR Growth Factor->GFR node18 5 Apoptosis node19 4 node20 1 node21 1 node22 1 SGK->node22 SGK SGK->FOXO3 node23 DJ-1 node23->PTEN node23->node12 node24 2 BAD->Apoptosis BAD->node24 BAD node25 3 p27->Apoptosis p27->node25 p27 node26 6 GSK3->Apoptosis GSK3->node26 GSK3 node27 10 peroxisome proliferator-activated receptor gamma PPARG PPARG->PTEN PPARG->node27 PPARG FAK->node7 ? node7->node6 ERK1/2 node7->SGK Transcription node7->Transcription Proliferation Transcription->Proliferation FOXO1->node19 FOXO1 FOXO1->Transcription FOXO3->node21 FOXO3 FOXO3->Transcription FOXO4->node20 FOXO4 FOXO4->Transcription GFR->node1 GFR GFR->node5 ITGB ITGB->SHC1 PIP3->PTEN PIP3->node9 PIP3 PIP3->PDK1 PIP2 PIP2->PTEN PIP2->PI3K p53->PTEN p53->node18 p53 p53->Apoptosis p53->node7 print "