Protein: Q96SB4

UniprotKB AC UniprotKB ID Gene name Full name Species Curated set
Q96SB4 (Uniprot) SRPK1_HUMAN SRPK1 SRSF protein kinase 1 human No
Uniprot: Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing. Plays a central role in the regulatory network for splicing, controlling the intranuclear distribution of splicing factors in interphase cells and the reorganization of nuclear speckles during mitosis. Can influence additional steps of mRNA maturation, as well as other cellular activities, such as chromatin reorganization in somatic and sperm cells and cell cycle progression. Isoform 2 phosphorylates SFRS2, ZRSR2, LBR and PRM1. Isoform 2 phosphorylates SRSF1 using a directional (C-terminal to N-terminal) and a dual-track mechanism incorporating both processive phosphorylation (in which the kinase stays attached to the substrate after each round of phosphorylation) and distributive phosphorylation steps (in which the kinase and substrate dissociate after each phosphorylation event). The RS domain of SRSF1 binds first to a docking groove in the large lobe of the kinase domain of SRPK1. This induces certain structural changes in SRPK1 and/or RRM2 domain of SRSF1, allowing RRM2 to bind the kinase and initiate phosphorylation. The cycles continue for several phosphorylation steps in a processive manner (steps 1-8) until the last few phosphorylation steps (approximately steps 9-12). During that time, a mechanical stress induces the unfolding of the beta-4 motif in RRM2, which then docks at the docking groove of SRPK1. This also signals RRM2 to begin to dissociate, which facilitates SRSF1 dissociation after phosphorylation is completed. Isoform 2 can mediate hepatitis B virus (HBV) core protein phosphorylation. It plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles. Isoform 1 and isoform 2 can induce splicing of exon 10 in MAPT/TAU. The ratio of isoform 1/isoform 2 plays a decisive role in determining cell fate in K-562 leukaemic cell line: isoform 2 favors proliferation where as isoform 1 favors differentiation. more..
MoonDB Dissimilar Functions
GO ID 1 Function 1 Module ID 1 GO ID 2 Function 2 Module ID 2 Association Probability (PrOnto) Interaction Probability (PrOnto)
GO:0036211 protein modification process 25, 171, 423, 483, 499 GO:0016070 RNA metabolic process 75, 689 5.81e-04 8.44e-05
GO:0019538 protein metabolic process 129, 164, 376, 404, 474, 728 GO:0016070 RNA metabolic process 75, 689 5.15e-08 2.82e-13
GO:0019538 protein metabolic process 129, 164, 376, 404, 474, 728 GO:0000377 RNA splicing, via transesterification reactions with bulged adenosine as nucleophile 353 1.88e-02 4.66e-37
GO:0007165 signal transduction 141 GO:0016070 RNA metabolic process 75, 689 3.11e-78 2.75e-26
GO:0007165 signal transduction 141 GO:0000377 RNA splicing, via transesterification reactions with bulged adenosine as nucleophile 353 4.83e-02 1.79e-71
GO:0007165 signal transduction 141 GO:0006139 nucleobase-containing compound metabolic process 356 1.10e-111 5.07e-25
GO:0007165 signal transduction 141 GO:0006725 cellular aromatic compound metabolic process 585 5.44e-126 5.27e-27
Biological Processes
Module ID (MoonGO) GO ID (BP) GO Name
25 GO:0006464 cellular protein modification process
25 GO:0010467 gene expression
25 GO:0060255 regulation of macromolecule metabolic process
25 GO:0007165 signal transduction
45 GO:0071495 cellular response to endogenous stimulus
45 GO:0071310 cellular response to organic substance
45 GO:0032270 positive regulation of cellular protein metabolic process
45 GO:0006468 protein phosphorylation
45 GO:0042325 regulation of phosphorylation
45 GO:0009966 regulation of signal transduction
75 GO:0016071 mRNA metabolic process
75 GO:0051252 regulation of RNA metabolic process
75 GO:0010468 regulation of gene expression
75 GO:0006351 transcription, DNA-templated
93 GO:0034645 cellular macromolecule biosynthetic process
93 GO:0034654 nucleobase-containing compound biosynthetic process
93 GO:0019538 protein metabolic process
93 GO:0051252 regulation of RNA metabolic process
93 GO:0010468 regulation of gene expression
96 GO:0016070 RNA metabolic process
96 GO:0010467 gene expression
124 GO:0010467 gene expression
124 GO:0090304 nucleic acid metabolic process
129 GO:0044267 cellular protein metabolic process
129 GO:0007165 signal transduction
141 GO:0035556 intracellular signal transduction
141 GO:0006468 protein phosphorylation
141 GO:0060255 regulation of macromolecule metabolic process
164 GO:0044267 cellular protein metabolic process
164 GO:0060255 regulation of macromolecule metabolic process
164 GO:0007165 signal transduction
171 GO:0006464 cellular protein modification process
171 GO:0035556 intracellular signal transduction
171 GO:0009966 regulation of signal transduction
173 GO:0034645 cellular macromolecule biosynthetic process
173 GO:0006464 cellular protein modification process
173 GO:0010467 gene expression
173 GO:0035556 intracellular signal transduction
173 GO:0090304 nucleic acid metabolic process
173 GO:0016310 phosphorylation
173 GO:0031325 positive regulation of cellular metabolic process
173 GO:0010604 positive regulation of macromolecule metabolic process
173 GO:0051173 positive regulation of nitrogen compound metabolic process
173 GO:0031326 regulation of cellular biosynthetic process
173 GO:0019219 regulation of nucleobase-containing compound metabolic process
203 GO:0016070 RNA metabolic process
203 GO:0010468 regulation of gene expression
217 GO:0060255 regulation of macromolecule metabolic process
217 GO:0007165 signal transduction
273 GO:0034645 cellular macromolecule biosynthetic process
273 GO:0044271 cellular nitrogen compound biosynthetic process
273 GO:0006464 cellular protein modification process
273 GO:0051252 regulation of RNA metabolic process
273 GO:0010468 regulation of gene expression
314 GO:0010467 gene expression
314 GO:0060255 regulation of macromolecule metabolic process
331 GO:0016070 RNA metabolic process
331 GO:0006464 cellular protein modification process
331 GO:0010467 gene expression
331 GO:0060255 regulation of macromolecule metabolic process
331 GO:0019219 regulation of nucleobase-containing compound metabolic process
337 GO:0022607 cellular component assembly
337 GO:0035556 intracellular signal transduction
337 GO:0006468 protein phosphorylation
337 GO:0060255 regulation of macromolecule metabolic process
353 GO:0000398 mRNA splicing, via spliceosome
356 GO:0034654 nucleobase-containing compound biosynthetic process
356 GO:0006468 protein phosphorylation
356 GO:0051252 regulation of RNA metabolic process
356 GO:2000112 regulation of cellular macromolecule biosynthetic process
356 GO:0010468 regulation of gene expression
356 GO:0007165 signal transduction
376 GO:0044267 cellular protein metabolic process
376 GO:0007165 signal transduction
404 GO:0044267 cellular protein metabolic process
404 GO:0007165 signal transduction
423 GO:0006464 cellular protein modification process
423 GO:0090304 nucleic acid metabolic process
423 GO:0060255 regulation of macromolecule metabolic process
430 GO:0019538 protein metabolic process
474 GO:0044267 cellular protein metabolic process
474 GO:0090304 nucleic acid metabolic process
474 GO:0060255 regulation of macromolecule metabolic process
483 GO:0006464 cellular protein modification process
483 GO:0010467 gene expression
483 GO:0009059 macromolecule biosynthetic process
483 GO:0090304 nucleic acid metabolic process
483 GO:0060255 regulation of macromolecule metabolic process
483 GO:0007165 signal transduction
493 GO:0016070 RNA metabolic process
493 GO:0010467 gene expression
499 GO:0006464 cellular protein modification process
499 GO:0060255 regulation of macromolecule metabolic process
546 GO:0051252 regulation of RNA metabolic process
546 GO:2000112 regulation of cellular macromolecule biosynthetic process
546 GO:0010468 regulation of gene expression
559 GO:0006355 regulation of transcription, DNA-templated
585 GO:0006139 nucleobase-containing compound metabolic process
649 GO:0016070 RNA metabolic process
649 GO:0010468 regulation of gene expression
658 GO:0019538 protein metabolic process
682 GO:0034645 cellular macromolecule biosynthetic process
682 GO:0006464 cellular protein modification process
682 GO:0035556 intracellular signal transduction
682 GO:0090304 nucleic acid metabolic process
682 GO:0010468 regulation of gene expression
682 GO:0019219 regulation of nucleobase-containing compound metabolic process
689 GO:0006396 RNA processing
689 GO:0051252 regulation of RNA metabolic process
689 GO:0010468 regulation of gene expression
714 GO:0016070 RNA metabolic process
714 GO:0010468 regulation of gene expression
725 GO:0051252 regulation of RNA metabolic process
725 GO:0010468 regulation of gene expression
728 GO:0044267 cellular protein metabolic process
728 GO:0031325 positive regulation of cellular metabolic process
728 GO:0010604 positive regulation of macromolecule metabolic process
728 GO:0051173 positive regulation of nitrogen compound metabolic process
728 GO:0051252 regulation of RNA metabolic process
728 GO:0010468 regulation of gene expression
728 GO:0007165 signal transduction
740 GO:0006355 regulation of transcription, DNA-templated
754 GO:0010605 negative regulation of macromolecule metabolic process
754 GO:0051252 regulation of RNA metabolic process
754 GO:0010468 regulation of gene expression
754 GO:0006366 transcription from RNA polymerase II promoter
758 GO:0016070 RNA metabolic process
758 GO:0034645 cellular macromolecule biosynthetic process
758 GO:0044271 cellular nitrogen compound biosynthetic process
758 GO:0044267 cellular protein metabolic process
758 GO:0009893 positive regulation of metabolic process
758 GO:0010468 regulation of gene expression
758 GO:0019219 regulation of nucleobase-containing compound metabolic process
759 GO:0016070 RNA metabolic process
Cellular Components
Module ID (MoonGO) GO ID (CC) GO Name
25 GO:0005829 cytosol
25 GO:0005634 nucleus
45 GO:0005829 cytosol
45 GO:0031981 nuclear lumen
45 GO:0005886 plasma membrane
65 GO:0012505 endomembrane system
65 GO:0016021 integral component of membrane
75 GO:0005829 cytosol
75 GO:0005654 nucleoplasm
93 GO:0005829 cytosol
93 GO:0005634 nucleus
96 GO:0005654 nucleoplasm
124 GO:0031981 nuclear lumen
129 GO:0005829 cytosol
129 GO:0070013 intracellular organelle lumen
141 GO:0005634 nucleus
171 GO:0005829 cytosol
171 GO:0005886 plasma membrane
173 GO:0005654 nucleoplasm
203 GO:0070013 intracellular organelle lumen
203 GO:0005634 nucleus
206 GO:0005829 cytosol
217 GO:0005829 cytosol
217 GO:0043232 intracellular non-membrane-bounded organelle
273 GO:0043232 intracellular non-membrane-bounded organelle
273 GO:0005654 nucleoplasm
314 GO:0005829 cytosol
314 GO:0005634 nucleus
331 GO:0005654 nucleoplasm
337 GO:0005829 cytosol
337 GO:0043232 intracellular non-membrane-bounded organelle
337 GO:0005634 nucleus
353 GO:0005654 nucleoplasm
356 GO:0005634 nucleus
376 GO:0005829 cytosol
376 GO:0005634 nucleus
404 GO:0005829 cytosol
404 GO:0012505 endomembrane system
404 GO:0031982 vesicle
423 GO:0005829 cytosol
423 GO:0005634 nucleus
436 GO:0031224 intrinsic component of membrane
483 GO:0005829 cytosol
483 GO:0031981 nuclear lumen
493 GO:0031981 nuclear lumen
499 GO:0005829 cytosol
499 GO:0031981 nuclear lumen
546 GO:0070013 intracellular organelle lumen
546 GO:0044428 nuclear part
559 GO:0031981 nuclear lumen
585 GO:0031981 nuclear lumen
649 GO:0070013 intracellular organelle lumen
649 GO:0005634 nucleus
658 GO:0005634 nucleus
682 GO:0005634 nucleus
689 GO:0005654 nucleoplasm
714 GO:0031981 nuclear lumen
725 GO:0005829 cytosol
725 GO:0031981 nuclear lumen
728 GO:0005829 cytosol
728 GO:0005634 nucleus
740 GO:0070013 intracellular organelle lumen
740 GO:0005634 nucleus
754 GO:0005654 nucleoplasm
758 GO:0005654 nucleoplasm
759 GO:0031981 nuclear lumen
GO ID (BP) GO Name Evidence Code (GO EC)
GO:0000245 spliceosomal complex assembly IBA
GO:0006468 protein phosphorylation IDA
GO:0007059 chromosome segregation IDA
GO:0008380 RNA splicing TAS
GO:0016032 viral process IEA
GO:0035092 sperm chromatin condensation TAS
GO:0035556 intracellular signal transduction IDA
GO:0045070 positive regulation of viral genome replication IDA
GO:0045071 negative regulation of viral genome replication IDA
GO:0045087 innate immune response IC
GO:0048024 regulation of mRNA splicing, via spliceosome TAS
GO:0050684 regulation of mRNA processing IDA
GO ID (CC) GO Name Evidence Code (GO EC)
GO:0005634 nucleus IDA
GO:0005737 cytoplasm IDA
GO:0005783 endoplasmic reticulum IEA
GO:0005829 cytosol IDA
GO:0005886 plasma membrane IDA
GO:0016363 nuclear matrix IEA
GO ID 1 Component 1 GO ID 2 Component 2 Association Probability (PrOnto) Interaction Probability (PrOnto)
GO:0005634 nucleus GO:0005783 endoplasmic reticulum 8.26e-33 3.22e-89
GO:0005634 nucleus GO:0005886 plasma membrane 5.35e-300 7.52e-165
Interactor Also a MoonDB EMF protein
RBM39_HUMAN No
CP135_HUMAN Yes: Q66GS9 (MoonDB)
LCE3D_HUMAN No
NCK2_HUMAN Yes: O43639 (MoonDB)
HS90B_HUMAN Yes: P08238 (MoonDB)
CEP19_HUMAN Yes: Q96LK0 (MoonDB)
ERR3_HUMAN No
NEMO_HUMAN Yes: Q9Y6K9 (MoonDB)
H2AY_HUMAN No
AURKC_HUMAN No
RNPS1_HUMAN No
ASXL1_HUMAN No
ZN444_HUMAN No
NXT2_HUMAN No
PPIL1_HUMAN No
RU17_HUMAN Yes: P08621 (MoonDB)
CLK1_HUMAN No
U2AFM_HUMAN No
RSRC1_HUMAN No
CLK4_HUMAN No
LC7L2_HUMAN No
ERBB2_HUMAN Yes: P04626 (MoonDB)
P53_HUMAN Yes: P04637 (MoonDB)
WDR55_HUMAN No
ECM1_HUMAN No
CK087_HUMAN No
CDKL3_HUMAN No
B3KMQ7_HUMAN No
ABCF1_HUMAN No
ADPRH_HUMAN No
ALKB3_HUMAN No
AMERL_HUMAN No
AOFB_HUMAN No
APEX1_HUMAN No
APMAP_HUMAN No
AR6P4_HUMAN No
ARGL1_HUMAN No
ASAH1_HUMAN No
AURKA_HUMAN No
BORG2_HUMAN No
BORG4_HUMAN No
CACB1_HUMAN No
CB39L_HUMAN No
CBX5_HUMAN Yes: P45973 (MoonDB)
CDK7_HUMAN No
CF201_HUMAN No
CHERP_HUMAN Yes: Q8IWX8 (MoonDB)
CHK2_HUMAN No
CI072_HUMAN No
CIAO1_HUMAN No
CK052_HUMAN No
CK063_HUMAN No
CLIC5_HUMAN No
CO039_HUMAN No
CP078_HUMAN No
CPSF5_HUMAN No
CR025_HUMAN No
CRFR1_HUMAN No
CSAG1_HUMAN No
DAW1_HUMAN No
DDX47_HUMAN No
DGCR8_HUMAN No
DHX8_HUMAN No
DNJC8_HUMAN No
DUS1L_HUMAN No
DUS6_HUMAN No
E41LA_HUMAN No
EIF3M_HUMAN No
EMIL1_HUMAN No
EPHA3_HUMAN No
F124A_HUMAN No
FA76B_HUMAN No
FAK1_HUMAN No
FBX15_HUMAN No
FGF12_HUMAN No
FGF1_HUMAN No
FHL1_HUMAN No
FKBP3_HUMAN No
FLOT1_HUMAN No
FOS_HUMAN No
GBRAP_HUMAN Yes: O95166 (MoonDB)
GBRL1_HUMAN No
GNPTG_HUMAN No
HBS1L_HUMAN No
HIRP3_HUMAN No
HMGN3_HUMAN No
IFIT5_HUMAN No
IKKA_HUMAN No
IMA1_HUMAN No
K1841_HUMAN No
KCAB1_HUMAN No
KCC2D_HUMAN No
KCNN2_HUMAN No
KPTN_HUMAN No
KRR1_HUMAN No
KS6B2_HUMAN No
L3R2A_HUMAN No
LAMC1_HUMAN No
LARP1_HUMAN No
LBR_HUMAN No
LIMK1_HUMAN No
LUC7L_HUMAN No
MAGB1_HUMAN No
MAPK5_HUMAN No
MBNL3_HUMAN No
MET14_HUMAN No
MK12_HUMAN No
MK14_HUMAN No
MKNK2_HUMAN No
MLP3A_HUMAN No
MTND_HUMAN No
NADAP_HUMAN No
NELFE_HUMAN No
NKAP_HUMAN No
NOL4L_HUMAN No
NOP16_HUMAN No
NOVA1_HUMAN No
NSE4A_HUMAN No
NSRP1_HUMAN No
OCEL1_HUMAN No
OD3L2_HUMAN No
OR6B3_HUMAN No
P2RX6_HUMAN No
PAK4_HUMAN No
PDPK1_HUMAN Yes: O15530 (MoonDB)
PELI1_HUMAN No
PELI2_HUMAN No
PEX19_HUMAN No
PGFRA_HUMAN No
PHF7_HUMAN No
PPIA_HUMAN No
PR38A_HUMAN No
PROF1_HUMAN No
PSA7_HUMAN No
RBM23_HUMAN No
RBM8A_HUMAN No
RBMS2_HUMAN No
RHG12_HUMAN No
RHG26_HUMAN No
RIMS4_HUMAN No
RM43_HUMAN No
ROA1_HUMAN No
RPAB1_HUMAN No
RSRC2_HUMAN No
RSRP1_HUMAN No
RT11_HUMAN No
SAFB1_HUMAN No
SAHH2_HUMAN No
SC23B_HUMAN No
SDS3_HUMAN No
SERF1_HUMAN No
SETD3_HUMAN No
SG11B_HUMAN No
SLAI2_HUMAN No
SMBT1_HUMAN No
SNUT2_HUMAN No
SPAS2_HUMAN No
SPB10_HUMAN No
SPXN4_HUMAN No
SREK1_HUMAN No
SRPK3_HUMAN No
SRS10_HUMAN No
SRS12_HUMAN No
SRSF1_HUMAN No
SRSF3_HUMAN No
SRSF6_HUMAN No
SRSF7_HUMAN No
SRSF8_HUMAN No
STAU1_HUMAN No
STK26_HUMAN No
TAAR8_HUMAN No
TAF1B_HUMAN No
TCAL2_HUMAN No
TFEB_HUMAN No
TR10C_HUMAN No
TRA2B_HUMAN No
TRI65_HUMAN No
TULP2_HUMAN No
U2AF1_HUMAN No
UB2E2_HUMAN Yes: Q96LR5 (MoonDB)
UBD_HUMAN No
VANG1_HUMAN No
VDR_HUMAN Yes: P11473 (MoonDB)
VGFR1_HUMAN No
WDR1_HUMAN No
YPEL2_HUMAN No
YPEL3_HUMAN No
YTDC1_HUMAN No
ZKSC8_HUMAN No
ZMY11_HUMAN No
ZN321_HUMAN No
ZN514_HUMAN No
ZRAB2_HUMAN No
PMID Article Title
8208298 A serine kinase regulates intracellular localization of splicing factors in the cell cycle.
9237760 A protein related to splicing factor U2AF35 that interacts with U2AF65 and SR proteins in splicing of pre-mRNA.
10049757 SRPK1 and LBR protein kinases show identical substrate specificities.
10390541 SR protein-specific kinase 1 is highly expressed in testis and phosphorylates protamine 1.
11509566 Cloning and characterization of an alternatively spliced form of SR protein kinase 1 that interacts specifically with scaffold attachment factor-B.
12134018 Identification of SRPK1 and SRPK2 as the major cellular protein kinases phosphorylating hepatitis B virus core protein.
12565829 Protein kinase CK2 phosphorylates and activates the SR protein-specific kinase 1.
14555757 Processive phosphorylation of alternative splicing factor/splicing factor 2.
14574404 The DNA sequence and analysis of human chromosome 6.
14702039 Complete sequencing and characterization of 21,243 full-length human cDNAs.
15034300 Identification of toposome, a novel multisubunit complex containing topoisomerase IIalpha.
15489334 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).
16122776 Suppression of hepatitis B virus replication by SRPK1 and SRPK2 via a pathway independent of the phosphorylation of the viral core protein.
16209947 Interplay between SRPK and Clk/Sty kinases in phosphorylation of the splicing factor ASF/SF2 is regulated by a docking motif in ASF/SF2.
17081983 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.
17223538 SR protein kinase 1 is resilient to inactivation.
18155240 Ordered multi-site phosphorylation of the splicing factor ASF/SF2 by SRPK1.
18342604 A sliding docking interaction is essential for sequential and processive phosphorylation of an SR protein by SRPK1.
18669648 A quantitative atlas of mitotic phosphorylation.
18687337 Adaptable molecular interactions guide phosphorylation of the SR protein ASF/SF2 by SRPK1.
18691976 Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle.
19240134 Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperones.
19413330 Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach.
19477182 Regiospecific phosphorylation control of the SR protein ASF/SF2 by SRPK1.
19553338 Arginine methylation of the ICP27 RGG box regulates the functional interactions of ICP27 with SRPK1 and Aly/REF during herpes simplex virus 1 infection.
19674106 The enzymatic activity of SR protein kinases 1 and 1a is negatively affected by interaction with scaffold attachment factors B1 and 2.
19690332 Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.
19886675 Allosteric interactions direct binding and phosphorylation of ASF/SF2 by SRPK1.
20708644 The ratio of SRPK1/SRPK1a regulates erythroid differentiation in K562 leukaemic cells.
21157427 Acetylation and phosphorylation of SRSF2 control cell fate decision in response to cisplatin.
21205200 Serine-arginine protein kinases: a small protein kinase family with a large cellular presence.
21205204 Phosphorylation mechanism and structure of serine-arginine protein kinases.
21269460 Initial characterization of the human central proteome.
21406692 System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation.
23186163 Toward a comprehensive characterization of a human cancer cell phosphoproteome.
24275569 An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.
25944712 N-terminome analysis of the human mitochondrial proteome.
No results found.
Domain Name Domain ID Source
Prot_kinase_dom IPR000719 InterPro
Ser/Thr_kinase_AS IPR008271 InterPro
Kinase-like_dom_sf IPR011009 InterPro
Protein_kinase_ATP_BS IPR017441 InterPro
Pkinase PF00069 Pfam
PROTEIN_KINASE_ATP PS00107 PROSITE
PROTEIN_KINASE_ST PS00108 PROSITE
PROTEIN_KINASE_DOM PS50011 PROSITE
S45337 S45337 PIR
S_TKc SM00220 SMART
SSF56112 SSF56112 SUPFAM