AKT1_RAT - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: AKT1_RAT
• UniProt AC: P47196
• Protein Name: RAC-alpha serine/threonine-protein kinase
• Gene Name: Akt1
• Organism: Rattus norvegicus (Rat).
• Sequence Length: 480
• Subcellular Localization: Cytoplasm . Nucleus . Cell membrane. Nucleus after activation by integrin-linked protein kinase 1 (ILK1). Nuclear translocation is enhanced by interaction with TCL1A (By similarity). Phosphorylation on Tyr-176 by TNK2 results in its localization to t
• Protein Description: AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation (By similarity). Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity (By similarity). Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53 (By similarity).; AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation..
• Protein Sequence: MNDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIGYKERPQDVEQRESPLNNFSVAQCQLMKTERPRPNTFIIRCLQWTTVIERTFHVETPEEREEWTTAIQTVADGLKRQEEETMDFRSGSPSDNSGAEEMEVALAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKILKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLSRERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGIKDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILMEEIRFPRTLGPEAKSLLSGLLKKDPTQRLGGGSEDAKEIMQHRFFANIVWQDVYEKKLSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA

Overview of Protein Modification Sites with Functional and Structural Information

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
14	Acetylation	VKEGWLHKRGEYIKT EECCCCCCCCCCCCC	60.99	-
20	Acetylation	HKRGEYIKTWRPRYF CCCCCCCCCCCCEEE	40.93	-
34	Phosphorylation	FLLKNDGTFIGYKER EEECCCCCEEEEECC	18.23	43091
122	Phosphorylation	EETMDFRSGSPSDNS HHHCCCCCCCCCCCC	43.55	23712012
124	Phosphorylation	TMDFRSGSPSDNSGA HCCCCCCCCCCCCCH	23.60	23712012
126	Phosphorylation	DFRSGSPSDNSGAEE CCCCCCCCCCCCHHH	51.63	27097102
126	O-linked_Glycosylation	DFRSGSPSDNSGAEE CCCCCCCCCCCCHHH	51.63	-
129	Phosphorylation	SGSPSDNSGAEEMEV CCCCCCCCCHHHHHH	44.35	23712012
129	O-linked_Glycosylation	SGSPSDNSGAEEMEV CCCCCCCCCHHHHHH	44.35	-
146	Phosphorylation	AKPKHRVTMNEFEYL CCCCCEECHHHHHHH	17.78	23984901
176	Phosphorylation	EKATGRYYAMKILKK ECCCCCCCHHHHHCC	10.00	-
305	O-linked_Glycosylation	EGIKDGATMKTFCGT CCCCCCCCCCCCCCC	25.40	-
308	Phosphorylation	KDGATMKTFCGTPEY CCCCCCCCCCCCHHH	17.21	14993198
312	O-linked_Glycosylation	TMKTFCGTPEYLAPE CCCCCCCCHHHHCHH	17.71	-
312	Phosphorylation	TMKTFCGTPEYLAPE CCCCCCCCHHHHCHH	17.71	22108457
315	Phosphorylation	TFCGTPEYLAPEVLE CCCCCHHHHCHHHHC	14.90	11319
448	Phosphorylation	EFTAQMITITPPDQD HCEEEEEEECCCCCC	17.29	-
450	Phosphorylation	TAQMITITPPDQDDS EEEEEEECCCCCCCC	21.81	29779826
473	Phosphorylation	RPHFPQFSYSASGTA CCCCCCCCCCCCCCC	16.96	14993198
473	O-linked_Glycosylation	RPHFPQFSYSASGTA CCCCCCCCCCCCCCC	16.96	28017896
474	Phosphorylation	PHFPQFSYSASGTA- CCCCCCCCCCCCCC-	15.00	28689409
475	Phosphorylation	HFPQFSYSASGTA-- CCCCCCCCCCCCC--	18.11	28689409
477	Phosphorylation	PQFSYSASGTA---- CCCCCCCCCCC----	30.64	28689409
479	Phosphorylation	FSYSASGTA------ CCCCCCCCC------	27.05	28689409

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
34	T	Phosphorylation	Kinase	PRKCZ	P09217	GPS
176	Y	Phosphorylation	Kinase	TNK2	Q5U2X5	Uniprot
308	T	Phosphorylation	Kinase	PRKCE	P16054	GPS
308	T	Phosphorylation	Kinase	PDPK1	O55173	Uniprot
308	T	Phosphorylation	Kinase	IKKE	-	Uniprot
308	T	Phosphorylation	Kinase	TBK1	-	Uniprot
450	T	Phosphorylation	Kinase	MTOR	P42346	Uniprot
473	S	Phosphorylation	Kinase	PRKCA	P17252	GPS
473	S	Phosphorylation	Kinase	PKCA	P05696	PSP
473	S	Phosphorylation	Kinase	PRKCE	P16054	GPS
473	S	Phosphorylation	Kinase	MTOR	P42346	Uniprot
473	S	Phosphorylation	Kinase	IKKE	-	Uniprot
473	S	Phosphorylation	Kinase	TBK1	-	Uniprot

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
14	K	Acetylation	Deacetylated at Lys-14 and Lys-20 by SIRT1.	-
14	K	Acetylation	Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B.	-
20	K	Acetylation	Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B.	-
20	K	Acetylation	Deacetylated at Lys-14 and Lys-20 by SIRT1.	-
48	K	ubiquitylation	When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome.	-
48	K	Phosphorylation	When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome.	-
48	K	ubiquitylation	Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination.	-
284	K	ubiquitylation	Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation (By similarity).	-
284	K	Phosphorylation	Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation (By similarity).	-
305	T	Phosphorylation	O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1.	10400692
308	T	Phosphorylation	This phosphorylated form localizes to the cell membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation.	9632753
308	T	Phosphorylation	Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1.	9632753
308	T	Phosphorylation	Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity.	9632753
308	T	Phosphorylation	Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1 (By similarity).	9632753
308	T	Phosphorylation	O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1.	9632753
308	T	Phosphorylation	Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase.	9632753
312	T	Phosphorylation	O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1.	10400692
473	S	Phosphorylation	This phosphorylated form localizes to the cell membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation.	9632753
473	S	Phosphorylation	Ser-473 phosphorylation is enhanced by signaling through activated FLT3 (By similarity).	9632753
473	S	Phosphorylation	Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1.	9632753
473	S	Phosphorylation	Ser-473 is dephosphorylated by PHLPP (By similarity).	9632753
473	S	Phosphorylation	Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling (By similarity).	9632753
473	S	Phosphorylation	Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity.	9632753
473	S	Phosphorylation	Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1 (By similarity).	9632753
473	S	Phosphorylation	O-GlcNAcylation at Ser-473 also probably interferes with phosphorylation at this site.	9632753
473	S	Phosphorylation	Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase.	9632753

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Oops, there are no SNP-PTM records of AKT1_RAT !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
GSK3B_RAT	Gsk3b	physical	15632182
SH2B2_RAT	Sh2b2	physical	16141217
ARBK1_RAT	Adrbk1	physical	16142243
GSK3B_RAT	Gsk3b	physical	16142243
G3P_RAT	Gapdh	physical	20488185
GSK3A_RAT	Gsk3a	physical	10995739
FOXO3_HUMAN	FOXO3	physical	10995739

Drug and Disease Associations

• Kegg Drug
• DrugBank
• There are no disease associations of PTM sites.