Egulation is the liver kinase B (LKB1 also known as STK11). LKB1 is an important tumor suppressor and gatekeeper mutations of LKB1 cause the rare Peutz-Jeghers Syndrome (PJS) which is a cancer-prone syndrome [191]. LKB1 is a gatekeeper gene and mutations in LKB1 are involved in the formation of hamartomatous polyps in PJS patients. LKB1 is an upstream activator of 5’AMP-activated protein kinase (AMPK) which activates TSC2 that negatively regulates Necrostatin-1 web mTORC1 [192,193]. LKB1 is a critical regulator of cell polarity and energy/metabolism control and exerts it vast effects via diverse effectors [138,194,195]. AMPK is considered a metabolic gatekeeper important in many diseases including diabetes, cancer and neurologic disorders [196-203]. AMPK is activated by the diabetes drug metformin [193]. Hence metformin will indirectly suppress mTORC1 activity. Chronic overfeeding increases mTORC1 activity which in turn promotes adiposity and decreases lifespan and is also believe to enhance cancer growth [204,205]. Inhibiting mTORC1 activity by drugs such as metformin and otherwww.impactjournals.com/oncotargetdrugs (including rapamycin) may not only aid in the treatment of diabetics, but also improve cancer therapies and increase longevity [206-216]. Akt also phosphorylates PRAS40, an inhibitor of mTORC1, and by doing so, it prevents the ability of PRAS40 to suppress mTORC1 signalling (recently reviewed in [135-138]). Thus, this could be yet another mechanism by which Akt activates mTORC1. Moreover, PRAS40 is a substrate of mTORC1 itself, and mTORC1mediated phosphorylation of PRAS40 prevents inhibition of additional mTORC1 signaling [135-138,181]. Due to its negative BX795 site regulation of mTORC1, PRAS40 has been proposed to have gatekeeper anti-apoptotic functions [217]. Also Ras/Raf/MEK/ERK signaling positively impinges on mTORC1. Both p90Rsk-1 and ERK 1/2 phosphorylate TSC2, thus suppressing its inhibitory function [135-138,181]. Moreover, mTORC1 inhibition resulted in ERK 1/2 activation, through p70S6K/PI3K/ Ras/Raf/MEK [183]. The relationship between Akt and mTOR is further complicated by the existence of the mTOR/Rictor complex (mTORC2), which, in some cell types, displays rapamycin-insensitive activity. mTORC2 is comprised of rapamycin insensitive companion of mTOR (Rictor), mTOR, DEPTOR, mLST8, Stress activated protein kinase INteracting protein 1 (SIN1) and protein observed with Rictor (Protor). mTORC2 phosphorylates Akt on S473 in vitro which facilitates T308 phosphorylation [185]. Thus, mTORC2 can function as the elusive PDK-2 which phosphorylates Akt-1 on S473 in response to growth factor stimulation [186,218]. Akt and mTOR are linked to each other via positive and negative regulatory circuits, which restrain their simultaneous hyperactivation through mechanisms involving p70S6K and PI3K [135-138,181]. Assuming that equilibrium exists between these two complexes, when the mTORC1 complex is formed, it could antagonize the formation of the mTORC2 complex and reduce Akt activity [180,181]. Thus, at least in principle, inhibition of the mTORC1 complex could result in Akt hyperactivation. This is one problem associated with therapeutic approaches using rapamycin or modified rapamycins (rapalogs) that block some, but not all, actions of mTOR. mTOR is a 289-kDa S/T kinase. mTOR was the first identified member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family [135-138,219]. Recently mTOR has been shown to be cell cycle regulated [220,221]. mT.Egulation is the liver kinase B (LKB1 also known as STK11). LKB1 is an important tumor suppressor and gatekeeper mutations of LKB1 cause the rare Peutz-Jeghers Syndrome (PJS) which is a cancer-prone syndrome [191]. LKB1 is a gatekeeper gene and mutations in LKB1 are involved in the formation of hamartomatous polyps in PJS patients. LKB1 is an upstream activator of 5’AMP-activated protein kinase (AMPK) which activates TSC2 that negatively regulates mTORC1 [192,193]. LKB1 is a critical regulator of cell polarity and energy/metabolism control and exerts it vast effects via diverse effectors [138,194,195]. AMPK is considered a metabolic gatekeeper important in many diseases including diabetes, cancer and neurologic disorders [196-203]. AMPK is activated by the diabetes drug metformin [193]. Hence metformin will indirectly suppress mTORC1 activity. Chronic overfeeding increases mTORC1 activity which in turn promotes adiposity and decreases lifespan and is also believe to enhance cancer growth [204,205]. Inhibiting mTORC1 activity by drugs such as metformin and otherwww.impactjournals.com/oncotargetdrugs (including rapamycin) may not only aid in the treatment of diabetics, but also improve cancer therapies and increase longevity [206-216]. Akt also phosphorylates PRAS40, an inhibitor of mTORC1, and by doing so, it prevents the ability of PRAS40 to suppress mTORC1 signalling (recently reviewed in [135-138]). Thus, this could be yet another mechanism by which Akt activates mTORC1. Moreover, PRAS40 is a substrate of mTORC1 itself, and mTORC1mediated phosphorylation of PRAS40 prevents inhibition of additional mTORC1 signaling [135-138,181]. Due to its negative regulation of mTORC1, PRAS40 has been proposed to have gatekeeper anti-apoptotic functions [217]. Also Ras/Raf/MEK/ERK signaling positively impinges on mTORC1. Both p90Rsk-1 and ERK 1/2 phosphorylate TSC2, thus suppressing its inhibitory function [135-138,181]. Moreover, mTORC1 inhibition resulted in ERK 1/2 activation, through p70S6K/PI3K/ Ras/Raf/MEK [183]. The relationship between Akt and mTOR is further complicated by the existence of the mTOR/Rictor complex (mTORC2), which, in some cell types, displays rapamycin-insensitive activity. mTORC2 is comprised of rapamycin insensitive companion of mTOR (Rictor), mTOR, DEPTOR, mLST8, Stress activated protein kinase INteracting protein 1 (SIN1) and protein observed with Rictor (Protor). mTORC2 phosphorylates Akt on S473 in vitro which facilitates T308 phosphorylation [185]. Thus, mTORC2 can function as the elusive PDK-2 which phosphorylates Akt-1 on S473 in response to growth factor stimulation [186,218]. Akt and mTOR are linked to each other via positive and negative regulatory circuits, which restrain their simultaneous hyperactivation through mechanisms involving p70S6K and PI3K [135-138,181]. Assuming that equilibrium exists between these two complexes, when the mTORC1 complex is formed, it could antagonize the formation of the mTORC2 complex and reduce Akt activity [180,181]. Thus, at least in principle, inhibition of the mTORC1 complex could result in Akt hyperactivation. This is one problem associated with therapeutic approaches using rapamycin or modified rapamycins (rapalogs) that block some, but not all, actions of mTOR. mTOR is a 289-kDa S/T kinase. mTOR was the first identified member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family [135-138,219]. Recently mTOR has been shown to be cell cycle regulated [220,221]. mT.
http://calcium-channel.com
Calcium Channel
