8.A.104. The 5'-AMP-activated protein kinase (AMPK) Family
This family includes the catalytic subunits of AMP-activated protein kinases (AMPK), energy sensor protein kinases that play key roles in regulating cellular energy metabolism. Some of these proteins include an N-terminal PKc-like superfamily domain and a C-terminal AMPKA_C-like domain, but other members have only the N-terminal PKc domain. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes in mammals (Egan et al. 2011). It acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm (McGee et al. 2008). It also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1 (Hallows et al. 2003). It plays a role in the differential regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and PIK3R4) complexes in response to glucose starvation, and can inhibit the non-autophagy complex by phosphorylating PIK3C3 while activating the pro-autophagy complex by phosphorylating BECN1.
A review summarizes the role of AMPK in the regulation of renal epithelial transport, updates the growing list of AMPK transport protein targets and discusses the regulatory mechanisms involved (Pastor-Soler and Hallows 2012). It couples membrane transport to the metabolic status of epithelial tissues like the kidney. AMPK is also involved in the coordination of hormonal, inflammatory, and other cellular stress pathway signals to produce an integrated effect on tubular transport (Pastor-Soler and Hallows 2012). Mackenzie and Elliott 2014 review the roll of AMPK in glucose uptake and focus on a mechanism that operates via an insulin-dependent pathway. Doxorubicin-induced cardiotoxicity through SIRT1 (AMPK) loss potentiates overproduction of exosomes in cardiomyocytes (Zhang et al. 2024).
References:
5'-Monophosphate-activated protein kinase (AMPK, PRKAA, AMPK2) of 552 aas. See family description for detais of its regulation of transport.
AMPK of Homo sapiens
RAC-α ser/thr kinase, Akt1 (PKB, RAC) of 480 aas. AKT1, AKT2 amd ALT3 regulate glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport (Kane et al. 2002). The AKT1 isoform has a more specific role in cell motility and proliferation (Enomoto et al. 2005). Acquired AKT-inhibitor resistance is mediated by ATP-binding cassette transporters in endometrial carcinoma (Takagi et al. 2023).
Akt1 of Homo sapiens
Calcium/calmodulin-dependent protein kinase type II, subunit alpha, CAMKIIA, of 478 aas and 0 TMSs. It regulates ion channel activities (see TC#s 1.A.1.20.6 and 1.A.17.1.1) (Ko et al. 2020). In addition, it functions autonomously after Ca2+/calmodulin-binding and autophosphorylation, and is involved in synaptic plasticity, neurotransmitter release and long-term potentiation. It is a member of the NMDAR signaling complex in excitatory synapses and regulates NMDAR-dependent potentiation of the AMPAR and therefore excitatory synaptic transmission, and it regulates dendritic spine development (Stephenson et al. 2017).
CAMKIIA of Homo sapiens
Calcium/calmodulin-dependent protein kinase type II, subunit gamma, CAMK2G, of 558 aas and 1 - 3 TMSs. It functions autonomously after Ca2+/calmodulin-binding and autophosphorylation, and is involved in sarcoplasmic reticulum Ca2+ transport in skeletal muscle and slow twitch muscle (Rose et al. 2006). In fast-twitch muscle, it participates in the control of Ca2+ release from the SR through phosphorylation of the ryanodine receptor-coupling factor triadin (TC# 8.A.28.1.3) (Proietti Onori et al. 2018).
CAMK2G of Homo sapiens
Protein kiinase of 554 aas and 3 TMSs. Unusual features and localization of the membrane kinome, including 10 membrane associated protein kinases of Trypanosoma brucei have been described and discussed (Jensen et al. 2021).
Protein kinase of Trypanosoma brucei brucei
Sodium ion-activated kinase, SIK1, of 783 aas and 1 TMS at residue ~220. The triad Nax (TC# 1.A.1.10.22)/SIK/Na+,K+-ATPase (TC# 3.A.3.1.1) contributes to kidney injury and salt-sensitive hypertension (Gonsalez et al. 2023).
SIK1 of Homo sapiens
Death-associated protein kinase 1, DAPK1 of 1430 aas and 0 TMSs. It is a calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. Regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. It phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. It acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex, and it phosphorylates GRINB at Ser-1303, inducing injurious Ca2+ influx through NMDA receptor channels, resulting in irreversible neuronal death (Makgoo et al. 2023). DAPK1 plays a role in the pathogenesis of neurodevelopmental and neurodegenerative diseases (Tian et al. 2023).
DAPK1 of Homo sapiens
Mitochondrial Ser/Thr protein kinase of 581 aas and as many as 6 possible TMSs about equally spaced throughout it's length, PINK1. Abberrant activation of adenine nucleotide translocase 3 (TC# 2.a.1.75.8) promotes progression and chemoresistance in multiple myeloma dependent on PINK1 transport (Hu et al. 2025).
PINL1 of Homo sapiens
Calcium/calmodulin-dependent protein kinase kinase 2 isoform 1, STO-609, of 588 aas and 1 N-termnal TMS. It inhibits nicotine-induced currents and intracellular calcium increase in insect neurosecretory cells (Taha et al. 2024).
STO-609 of Homo sapiens
Camk, Camkl, AMPK protein kinase of 688 aas.
AMPK of Plasmopara halstedii
Serine/threonine-protein kinase SIK3 isoform X2of 1284 aas.
SIK3 of Labrus bergylta
Protein kinase C-β, PRKCB or PKCB or PRKCB1, of 671 aas and 0 or 1 TMSs. It participates in the regulation of glucose transport in adipocytes by negatively modulating the insulin-stimulated translocation of the glucose transporter SLC2A4/GLUT4. It also phosphorylates SLC2A1/GLUT1, promoting glucose uptake (Lee et al. 2015). It may also play a role in Meniere's disease (Lopez-Escamez et al. 2018).
PRKCB of Homo sapiens
Salt Overly Sensitive-2 (SOS2) of 446 aas, possibly with 2 TMSs, but none at its N-terminus; a protein kinase. The salt stress-induced SALT-OVERLY-SENSITIVE (SOS) pathway in Arabidopsis thaliana involves the perception of a calcium signal by the SOS3 and SOS3-like CALCIUM-BINDING PROTEIN8 (SCaBP8; 5.b.1.1.8) calcium sensors, which then interact with and activate the SOS2 protein kinase, forming a complex at the plasma membrane that activates the SOS1 Na⁺/H⁺ exchanger (2.A.36.7.6) (Lin et al. 2014).
Plants
SOS2 of Arabidopsis thaliana (Mouse-ear cress)
Protein kinase domain containing protein of 886 aas with 2 or 3 N-terminal TMSs. Reveals homology of members of this family with 1.A.87.2.1, 9.B.15.1.1 and 9.B.45.1.3. all probably containing eukaryotic-type protein kinase domains. The N-terminal 130 aas are homologous to residues 111 - 243 of 9.A.54.3.1, an LMBR1-like protein.
Alveolata
PK domain protein of Perkinsus marinus
SpdA of 270 aas and 4 putative N-terminal TMSs. SpdA and SpdB (TC#9.B.106.1.3) are encoded on an 11-kbp multicopy plasmid, pSN22, isolated from Streptomyces nigrifaciens SN22. Both are homologous to DUF2637 domain-containing proteins, and both have 4 N-terminal TMSs. This plasmid is self-transmissible (conjugative), is maintained stably in S. lividans, and forms pocks in a wide range of Streptomyces strains. SpdA and SpdB are involved in pock formation (Kataoka et al. 1991). SpdA may function in intramycelial plasmid transfer (Mendes et al. 2000). SpdA (this entry) has a 4 TMS 100 residue sequence homologous to the 4 TMSs in TC# 8.A.104.1.8, but lacks the protein kinase domain of the latter. This 4 TMS sequence is not found in other members of this family. SpdA overlaps protein 8.A.104.1.8 but is not a member of family 8.A.104; it is homologous only in its short C-terminal region.
Actinobacteria
SpdA pf Streptomyces sp. SPB74 (B5G9R1)
Serine/Threonine protein kinase of 741 aas, 4 N-terminal TMSs, and possibly 2 or 3 central TMSs The kinase domain is like those of 9.A.15.1.1 and 9.B.45.1.3.
Actinobacteria
S/T protein kinase of Amycolatopsis mediterranei (D8HIS0)
Serine/threonine-protein kinase/endoribonuclease, IRE1 or ERN1, of 977 aas and 2 TMSs, one N-terminal and one centrally located in the protein. It acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR) (Yoshida et al. 2001; Ali et al. 2011). IRE1 acts to reposition lysosomes and protects cells from stress. Blos1 regulation by IRE1 promotes late endosome-mediated microautophagy of protein aggregates and protects cells from their cytotoxic effects (Bae et al. 2019). The stress-sensing domain of activated IRE1α forms helical filaments in narrow ER membrane tubes (Tran et al. 2021).
IRE1 of Homo sapiens