ID   CDN1B_CANLF             Reviewed;         198 AA.
AC   Q6SLL5;
DT   26-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT   05-JUL-2004, sequence version 1.
DT   25-MAY-2022, entry version 89.
DE   RecName: Full=Cyclin-dependent kinase inhibitor 1B;
DE   AltName: Full=Cyclin-dependent kinase inhibitor p27;
DE   AltName: Full=p27Kip1;
GN   Name=CDKN1B; Synonyms=KIP1;
OS   Canis lupus familiaris (Dog) (Canis familiaris).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis.
OX   NCBI_TaxID=9615;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Liver;
RA   Spee B., Penning L.C., Rothuizen J.;
RT   "Differential gene expression of regenerative and fibrotic pathways in
RT   canine hepatic portosystemic shunt and portal vein hypoplasia.";
RL   Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
CC   -!- FUNCTION: Important regulator of cell cycle progression. Inhibits the
CC       kinase activity of CDK2 bound to cyclin A, but has little inhibitory
CC       activity on CDK2 bound to SPDYA. Involved in G1 arrest. Potent
CC       inhibitor of cyclin E- and cyclin A-CDK2 complexes. Forms a complex
CC       with cyclin type D-CDK4 complexes and is involved in the assembly,
CC       stability, and modulation of CCND1-CDK4 complex activation. Acts either
CC       as an inhibitor or an activator of cyclin type D-CDK4 complexes
CC       depending on its phosphorylation state and/or stoichometry.
CC       {ECO:0000250|UniProtKB:P46527}.
CC   -!- SUBUNIT: Forms a ternary complex composed of CCNE1, CDK2 and CDKN1B.
CC       Interacts directly with CCNE1; the interaction is inhibited by CDK2-
CC       dependent phosphorylation on Thr-187. Interacts with COPS5, subunit of
CC       the COP9 signalosome complex; the interaction leads to CDKN1B
CC       degradation. Interacts with NUP50; the interaction leads to nuclear
CC       import and degradation of phosphorylated CDKN1B. Interacts with CCND1
CC       and SNX6 (By similarity). Interacts (Thr-198-phosphorylated form) with
CC       14-3-3 proteins, binds strongly YWHAQ, weakly YWHAE and YWHAH, but not
CC       YWHAB nor YWHAZ; the interaction with YWHAQ results in translocation to
CC       the cytoplasm. Interacts with AKT1 and LYN; the interactions lead to
CC       cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of
CC       cell cycle arrest. Forms a ternary complex with CCNA2 and CDK2; CDKN1B
CC       inhibits the kinase activity of CDK2 through conformational
CC       rearrangements. Interacts (unphosphorylated form) with CDK2. Forms a
CC       complex with CDK2 and SPDYA, but does not directly interact with SPDYA.
CC       Forms a ternary complex composed of cyclin D, CDK4 and CDKN1B.
CC       Interacts (phosphorylated on Tyr-88 and Tyr-89) with CDK4; the
CC       interaction is required for cyclin D and CDK4 complex assembly, induces
CC       nuclear translocation and activates the CDK4 kinase activity. Interacts
CC       with GRB2. Interacts with PIM1. Identified in a complex with SKP1, SKP2
CC       and CKS1B. Interacts with UHMK1; the interaction leads to cytoplasmic
CC       mislocation, phosphorylation of CDKN1B and inhibition of cell cycle
CC       arrest. Interacts also with CDK1. Dephosphorylated on Thr-187 by PPM1H,
CC       leading to CDKN1B stability (By similarity). {ECO:0000250,
CC       ECO:0000250|UniProtKB:P46527}.
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}. Cytoplasm {ECO:0000250}.
CC       Endosome {ECO:0000250}. Note=Nuclear and cytoplasmic in quiescent
CC       cells. AKT- or RSK-mediated phosphorylation on Thr-198, binds 14-3-3,
CC       translocates to the cytoplasm and promotes cell cycle progression.
CC       Mitogen-activated UHMK1 phosphorylation on Ser-10 also results in
CC       translocation to the cytoplasm and cell cycle progression.
CC       Phosphorylation on Ser-10 facilitates nuclear export. Translocates to
CC       the nucleus on phosphorylation of Tyr-88 and Tyr-89 (By similarity).
CC       Colocalizes at the endosome with SNX6; this leads to lysosomal
CC       degradation (By similarity). {ECO:0000250}.
CC   -!- DOMAIN: A peptide sequence containing only AA 28-79 retains substantial
CC       Kip1 cyclin A/CDK2 inhibitory activity. {ECO:0000250}.
CC   -!- PTM: Phosphorylated; phosphorylation occurs on serine, threonine and
CC       tyrosine residues. Phosphorylation on Ser-10 is the major site of
CC       phosphorylation in resting cells, takes place at the G(0)-G(1) phase
CC       and leads to protein stability. Phosphorylation on other sites is
CC       greatly enhanced by mitogens, growth factors, cMYC and in certain
CC       cancer cell lines. The phosphorylated form found in the cytoplasm is
CC       inactivate. Phosphorylation on Thr-198 is required for interaction with
CC       14-3-3 proteins. Phosphorylation on Thr-187, by CDK1 and CDK2 leads to
CC       protein ubiquitination and proteasomal degradation. Tyrosine
CC       phosphorylation promotes this process. Phosphorylation by PKB/AKT1 can
CC       be suppressed by LY294002, an inhibitor of the catalytic subunit of
CC       PI3K. Phosphorylation on Tyr-88 and Tyr-89 has no effect on binding
CC       CDK2, but is required for binding CDK4. Dephosphorylated on tyrosine
CC       residues by G-CSF (By similarity). Dephosphorylated on Thr-187 by
CC       PPM1H, leading to CDKN1B stability (By similarity).
CC       {ECO:0000250|UniProtKB:P46527}.
CC   -!- PTM: Ubiquitinated; in the cytoplasm by the KPC complex (composed of
CC       RNF123/KPC1 and UBAC1/KPC2) and, in the nucleus, by SCF(SKP2). The
CC       latter requires prior phosphorylation on Thr-187. Ubiquitinated; by a
CC       TRIM21-containing SCF(SKP2)-like complex; leads to its degradation (By
CC       similarity). {ECO:0000250}.
CC   -!- PTM: Subject to degradation in the lysosome. Interaction with SNX6
CC       promotes lysosomal degradation (By similarity). {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the CDI family. {ECO:0000305}.
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DR   EMBL; AY455798; AAR19221.1; -; mRNA.
DR   AlphaFoldDB; Q6SLL5; -.
DR   SMR; Q6SLL5; -.
DR   STRING; 9612.ENSCAFP00000019502; -.
DR   PaxDb; Q6SLL5; -.
DR   eggNOG; KOG4743; Eukaryota.
DR   InParanoid; Q6SLL5; -.
DR   Proteomes; UP000002254; Unplaced.
DR   GO; GO:0005768; C:endosome; IEA:UniProtKB-SubCell.
DR   GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0004861; F:cyclin-dependent protein serine/threonine kinase inhibitor activity; ISS:UniProtKB.
DR   GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR   GO; GO:0045736; P:negative regulation of cyclin-dependent protein serine/threonine kinase activity; ISS:UniProtKB.
DR   GO; GO:0042127; P:regulation of cell population proliferation; IEA:InterPro.
DR   Gene3D; 4.10.365.10; -; 1.
DR   InterPro; IPR003175; CDI_dom.
DR   InterPro; IPR044898; CDI_dom_sf.
DR   InterPro; IPR029843; CDKN1B.
DR   PANTHER; PTHR10265:SF9; PTHR10265:SF9; 1.
DR   Pfam; PF02234; CDI; 1.
PE   2: Evidence at transcript level;
KW   Cell cycle; Cytoplasm; Endosome; Nucleus; Phosphoprotein;
KW   Protein kinase inhibitor; Reference proteome; Ubl conjugation.
FT   CHAIN           1..198
FT                   /note="Cyclin-dependent kinase inhibitor 1B"
FT                   /id="PRO_0000190081"
FT   REGION          1..30
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          51..91
FT                   /note="Interaction with CDK2"
FT                   /evidence="ECO:0000250|UniProtKB:P46527"
FT   REGION          87..198
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           153..169
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000255"
FT   COMPBIAS        105..128
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        158..172
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         10
FT                   /note="Phosphoserine; by UHMK1"
FT                   /evidence="ECO:0000250|UniProtKB:P46527"
FT   MOD_RES         74
FT                   /note="Phosphotyrosine; by SRC"
FT                   /evidence="ECO:0000250|UniProtKB:P46527"
FT   MOD_RES         88
FT                   /note="Phosphotyrosine; by ABL, LYN and SRC"
FT                   /evidence="ECO:0000250|UniProtKB:P46527"
FT   MOD_RES         89
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:P46527"
FT   MOD_RES         157
FT                   /note="Phosphothreonine; by CaMK1, PKB/AKT1 and PIM1"
FT                   /evidence="ECO:0000250|UniProtKB:P46527"
FT   MOD_RES         170
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:P46414"
FT   MOD_RES         187
FT                   /note="Phosphothreonine; by PKB/AKT1, CDK1 and CDK2"
FT                   /evidence="ECO:0000250|UniProtKB:P46527"
FT   MOD_RES         198
FT                   /note="Phosphothreonine; by CaMK1, PKB/AKT1, RPS6KA1,
FT                   RPS6KA3 and PIM1"
FT                   /evidence="ECO:0000250|UniProtKB:P46527"
SQ   SEQUENCE   198 AA;  22117 MW;  636482DEA114A22B CRC64;
     MSNVRVSNGS PTSERRDAKQ AEYPKPSACR NLFGPVNHEE LTRDLEKHCI DMEEASQNKW
     NFDFQNHKPL EGKYEWQEVE KGSLPEFYYR PPRPPKGACK VPAQESQDVS GTRQAGPLLG
     SQANSEDTHL VDQKTDAPDS QTGLAEQCTG IRKRPATDDS SPQNKRANRT EENVSDGSPN
     AGSVEQTPKK PGLRRRQT