Development - Keratinocyte differentiation

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Keratinocyte differentiation

There are several pathways of keratinocytes differentiation. Calcium signaling is one of them.

Calcium activates its signaling pathways at least in part via Calcium-sensing receptor (CASR) [1], [2]. CASR is a G-protein alpha-q/11-coupled receptor. It stimulates the hydrolysis of Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) by activating Phospholipase C-beta 1 (PLC-beta 1) and Phospholipase C-gamma 1 (PLC-gamma 1) via v-src sarcoma viral oncogene homolog (c-Src) [3], [4], [5]. This leads to release of two second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 then activates IP3 receptor (IP3R) to release Ca('2+) from intracellular stores. Ca('2+) and DAG activates Protein kinase C, alpha (PKC-alpha), and DAG activates Protein kinase C, delta (PKC-delta) [5], [6], [7].

1,25-dihydroxycholecalciferol (Calcitriol) plays a modulatory role in Ca('2+) signaling and promotes keratinocyte differentiation [8], [9]. Calcitriol increases the expression of CASR and PLC-beta1 and PLC-gamma1, thus enhancing the sensitivity of the keratinocyte to Ca('2+)activation [8], [10]. In addition, Calcitriol induces Involucrin gene expression via vitamin D receptor (VDR) pathway [5].

Activated by Ca('2+) PKC-alpha induces V-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinase 1 (MEK1(MAP2K1)), Mitogen-activated protein kinase kinase 2 (MEK2(MAP2K2))/ Mitogen-activated protein kinases 1 and 3 (ERK1/2) signaling that regulates the granular cell stage of epidermal differentiation by enhancing expression of Loricrin, Filaggrin, and Transglutaminase-1 (TGM1) [6], [11].

Additionally, PKC-delta can increase Involicrin gene expression via v-Harvey rat sarcoma viral oncogene homolog (H-Ras) and several MAPK/MEKK cascades [7], [12].

The first cascade includes Mitogen-activated protein kinase kinase kinase 1 (MEKK1) which phosphorylates Mitogen-activated protein kinase kinase 3 (MEK3), thus triggers Mitogen activated protein kinase 13 (p38delta (MAPK13)) and Mitogen activated protein kinase 14 (p38alpha (MAPK14)) to increase Involucrin gene expression via CCAAT/enhancer binding protein, alpha (C/EBP alpha) and AP-1 proteins respectively [13], [14].

The second cascade includes mitogen-activated protein kinase kinase 7 (MEK7) and mitogen-activated protein kinase kinase 6 (MEK6), which are activated by MEKK1. Then these kinases phosphorylate p38alpha (MAPK14) and regulate Involucrin promoter activity via AP-1 transcription factors: Jun oncogene(c-Jun), FBJ murine osteosarcoma viral oncogene homolog (c-Fos) [13], [15], [16].

By the way, H-Ras/ MEKK1/ Mitogen-activated protein kinase kinase 7 (MEK7)/ Mitogen-activated protein kinase 8 (JNK1) cascade activates c-Jun, c-Fos and jun D proto-oncogene (JunD) which increase expression of Cystatin A [17], [18].

Mitogen-activated protein kinase kinase kinase 5 (ASK1) signaling pathway is also involved in keratinocyte differentiation. ASK1 activates TGM1, Loricrin, and Involucrin via Mitogen-activated protein kinase kinase 4 (MEK4)/ JNK1 and MEK3/ MEK6/ p38alpha (MAPK14) cascades [19].

Inhibitor of nuclear factor kappa-B kinase subunit alpha (IKK-alpha) is also required in keratinocytes differentiation. In this pathway, TGF-beta1 acts via TGF-beta receptor type I that phosphorylates and activates 2 SMAD proteins: SMAD family member 3 (SMAD3) and SMAD family member 2 (SMAD2). IKK-alpha interacts with SMAD2 and SMAD3 that activates expression of MAX dimerization protein 1 (MAD). Finally, MAD causes the cessation of cell proliferation associated with keratinocyte differentiation [20], [21].

Notch signaling can trigger two distinct pathways leading to keratinocyte differentiation. Both Notch homolog 1, translocation-associated (Drosophila) (Notch1) and Notch homolog 2 (Drosophila) (Notch2) induce Involucrin gene expression via Recombination signal binding protein for immunoglobulin kappa J region (RBP-Jkappa)-independent mechanism leading to keratinocyte differentiation [22]. In addition, Notch1 can increase expression another markers of differentiation: Keratin 1 and Keratin 10. This pathway is also RBP-Jkappa-independent. [22].

By the way, Notch1-induced RBP-Jkappa binds to the endogenous Cyclin-dependent kinase inhibitor 1A (p21) promoter and thus mediates Notch1-dependent keratinocyte growth arrest and stimulates differentiation [23].

References:

  1. Bikle DD, Ratnam A, Mauro T, Harris J, Pillai S
    Changes in calcium responsiveness and handling during keratinocyte differentiation. Potential role of the calcium receptor. The Journal of clinical investigation 1996 Feb 15;97(4):1085-93
  2. Tu CL, Chang W, Bikle DD
    The extracellular calcium-sensing receptor is required for calcium-induced differentiation in human keratinocytes. The Journal of biological chemistry 2001 Nov 2;276(44):41079-85
  3. Zhao Y, Sudol M, Hanafusa H, Krueger J
    Increased tyrosine kinase activity of c-Src during calcium-induced keratinocyte differentiation. Proceedings of the National Academy of Sciences of the United States of America 1992 Sep 1;89(17):8298-302
  4. Xie Z, Bikle DD
    Phospholipase C-gamma1 is required for calcium-induced keratinocyte differentiation. The Journal of biological chemistry 1999 Jul 16;274(29):20421-4
  5. Bikle DD, Oda Y, Xie Z
    Calcium and 1,25(OH)2D: interacting drivers of epidermal differentiation. The Journal of steroid biochemistry and molecular biology 2004 May;89-90(1-5):355-60
  6. Dlugosz AA, Cheng C, Williams EK, Dharia AG, Denning MF, Yuspa SH
    Alterations in murine keratinocyte differentiation induced by activated rasHa genes are mediated by protein kinase C-alpha. Cancer research 1994 Dec 15;54(24):6413-20
  7. Deucher A, Efimova T, Eckert RL
    Calcium-dependent involucrin expression is inversely regulated by protein kinase C (PKC)alpha and PKCdelta. The Journal of biological chemistry 2002 May 10;277(19):17032-40
  8. Pillai S, Bikle DD, Su MJ, Ratnam A, Abe J
    1,25-Dihydroxyvitamin D3 upregulates the phosphatidylinositol signaling pathway in human keratinocytes by increasing phospholipase C levels. The Journal of clinical investigation 1995 Jul;96(1):602-9
  9. Su MJ, Bikle DD, Mancianti ML, Pillai S
    1,25-Dihydroxyvitamin D3 potentiates the keratinocyte response to calcium. The Journal of biological chemistry 1994 May 20;269(20):14723-9
  10. Bikle DD, Tu CL, Xie Z, Oda Y
    Vitamin D regulated keratinocyte differentiation: role of coactivators. Journal of cellular biochemistry 2003 Feb 1;88(2):290-5
  11. Seo HR, Kwan YW, Cho CK, Bae S, Lee SJ, Soh JW, Chung HY, Lee YS
    PKCalpha induces differentiation through ERK1/2 phosphorylation in mouse keratinocytes. Experimental & molecular medicine 2004 Aug 31;36(4):292-9
  12. Ng DC, Shafaee S, Lee D, Bikle DD
    Requirement of an AP-1 site in the calcium response region of the involucrin promoter. The Journal of biological chemistry 2000 Aug 4;275(31):24080-8
  13. Efimova T, LaCelle P, Welter JF, Eckert RL
    Regulation of human involucrin promoter activity by a protein kinase C, Ras, MEKK1, MEK3, p38/RK, AP1 signal transduction pathway. The Journal of biological chemistry 1998 Sep 18;273(38):24387-95
  14. Efimova T, Deucher A, Kuroki T, Ohba M, Eckert RL
    Novel protein kinase C isoforms regulate human keratinocyte differentiation by activating a p38 delta mitogen-activated protein kinase cascade that targets CCAAT/enhancer-binding protein alpha. The Journal of biological chemistry 2002 Aug 30;277(35):31753-60
  15. Dashti SR, Efimova T, Eckert RL
    MEK7-dependent activation of p38 MAP kinase in keratinocytes. The Journal of biological chemistry 2001 Mar 16;276(11):8059-63
  16. Dashti SR, Efimova T, Eckert RL
    MEK6 regulates human involucrin gene expression via a p38alpha - and p38delta -dependent mechanism. The Journal of biological chemistry 2001 Jul 20;276(29):27214-20
  17. Takahashi H, Asano K, Kinouchi M, Ishida-Yamamoto A, Wuepper KD, Iizuka H
    Structure and transcriptional regulation of the human cystatin A gene. The 12-O-tetradecanoylphorbol-13-acetate (TPA) responsive element-2 site (-272 to -278) on cystatin A gene is critical for TPA-dependent regulation. The Journal of biological chemistry 1998 Jul 10;273(28):17375-80
  18. Takahashi H, Honma M, Ishida-Yamamoto A, Namikawa K, Kiyama H, Iizuka H
    Expression of human cystatin A by keratinocytes is positively regulated via the Ras/MEKK1/MKK7/JNK signal transduction pathway but negatively regulated via the Ras/Raf-1/MEK1/ERK pathway. The Journal of biological chemistry 2001 Sep 28;276(39):36632-8
  19. Sayama K, Hanakawa Y, Shirakata Y, Yamasaki K, Sawada Y, Sun L, Yamanishi K, Ichijo H, Hashimoto K
    Apoptosis signal-regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation. The Journal of biological chemistry 2001 Jan 12;276(2):999-1004
  20. Västrik I, Kaipainen A, Penttilä TL, Lymboussakis A, Alitalo R, Parvinen M, Alitalo K
    Expression of the mad gene during cell differentiation in vivo and its inhibition of cell growth in vitro. The Journal of cell biology 1995 Mar;128(6):1197-208
  21. Descargues P, Sil AK, Sano Y, Korchynskyi O, Han G, Owens P, Wang XJ, Karin M
    IKKalpha is a critical coregulator of a Smad4-independent TGFbeta-Smad2/3 signaling pathway that controls keratinocyte differentiation. Proceedings of the National Academy of Sciences of the United States of America 2008 Feb 19;105(7):2487-92
  22. Lefort K, Dotto GP
    Notch signaling in the integrated control of keratinocyte growth/differentiation and tumor suppression. Seminars in cancer biology 2004 Oct;14(5):374-86
  23. Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, Aster JC, Krishna S, Metzger D, Chambon P, Miele L, Aguet M, Radtke F, Dotto GP
    Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. The EMBO journal 2001 Jul 2;20(13):3427-36

  1. Bikle DD, Ratnam A, Mauro T, Harris J, Pillai S
    Changes in calcium responsiveness and handling during keratinocyte differentiation. Potential role of the calcium receptor. The Journal of clinical investigation 1996 Feb 15;97(4):1085-93
  2. Tu CL, Chang W, Bikle DD
    The extracellular calcium-sensing receptor is required for calcium-induced differentiation in human keratinocytes. The Journal of biological chemistry 2001 Nov 2;276(44):41079-85
  3. Zhao Y, Sudol M, Hanafusa H, Krueger J
    Increased tyrosine kinase activity of c-Src during calcium-induced keratinocyte differentiation. Proceedings of the National Academy of Sciences of the United States of America 1992 Sep 1;89(17):8298-302
  4. Xie Z, Bikle DD
    Phospholipase C-gamma1 is required for calcium-induced keratinocyte differentiation. The Journal of biological chemistry 1999 Jul 16;274(29):20421-4
  5. Bikle DD, Oda Y, Xie Z
    Calcium and 1,25(OH)2D: interacting drivers of epidermal differentiation. The Journal of steroid biochemistry and molecular biology 2004 May;89-90(1-5):355-60
  6. Dlugosz AA, Cheng C, Williams EK, Dharia AG, Denning MF, Yuspa SH
    Alterations in murine keratinocyte differentiation induced by activated rasHa genes are mediated by protein kinase C-alpha. Cancer research 1994 Dec 15;54(24):6413-20
  7. Deucher A, Efimova T, Eckert RL
    Calcium-dependent involucrin expression is inversely regulated by protein kinase C (PKC)alpha and PKCdelta. The Journal of biological chemistry 2002 May 10;277(19):17032-40
  8. Pillai S, Bikle DD, Su MJ, Ratnam A, Abe J
    1,25-Dihydroxyvitamin D3 upregulates the phosphatidylinositol signaling pathway in human keratinocytes by increasing phospholipase C levels. The Journal of clinical investigation 1995 Jul;96(1):602-9
  9. Su MJ, Bikle DD, Mancianti ML, Pillai S
    1,25-Dihydroxyvitamin D3 potentiates the keratinocyte response to calcium. The Journal of biological chemistry 1994 May 20;269(20):14723-9
  10. Bikle DD, Tu CL, Xie Z, Oda Y
    Vitamin D regulated keratinocyte differentiation: role of coactivators. Journal of cellular biochemistry 2003 Feb 1;88(2):290-5
  11. Seo HR, Kwan YW, Cho CK, Bae S, Lee SJ, Soh JW, Chung HY, Lee YS
    PKCalpha induces differentiation through ERK1/2 phosphorylation in mouse keratinocytes. Experimental & molecular medicine 2004 Aug 31;36(4):292-9
  12. Ng DC, Shafaee S, Lee D, Bikle DD
    Requirement of an AP-1 site in the calcium response region of the involucrin promoter. The Journal of biological chemistry 2000 Aug 4;275(31):24080-8
  13. Efimova T, LaCelle P, Welter JF, Eckert RL
    Regulation of human involucrin promoter activity by a protein kinase C, Ras, MEKK1, MEK3, p38/RK, AP1 signal transduction pathway. The Journal of biological chemistry 1998 Sep 18;273(38):24387-95
  14. Efimova T, Deucher A, Kuroki T, Ohba M, Eckert RL
    Novel protein kinase C isoforms regulate human keratinocyte differentiation by activating a p38 delta mitogen-activated protein kinase cascade that targets CCAAT/enhancer-binding protein alpha. The Journal of biological chemistry 2002 Aug 30;277(35):31753-60
  15. Dashti SR, Efimova T, Eckert RL
    MEK7-dependent activation of p38 MAP kinase in keratinocytes. The Journal of biological chemistry 2001 Mar 16;276(11):8059-63
  16. Dashti SR, Efimova T, Eckert RL
    MEK6 regulates human involucrin gene expression via a p38alpha - and p38delta -dependent mechanism. The Journal of biological chemistry 2001 Jul 20;276(29):27214-20
  17. Takahashi H, Asano K, Kinouchi M, Ishida-Yamamoto A, Wuepper KD, Iizuka H
    Structure and transcriptional regulation of the human cystatin A gene. The 12-O-tetradecanoylphorbol-13-acetate (TPA) responsive element-2 site (-272 to -278) on cystatin A gene is critical for TPA-dependent regulation. The Journal of biological chemistry 1998 Jul 10;273(28):17375-80
  18. Takahashi H, Honma M, Ishida-Yamamoto A, Namikawa K, Kiyama H, Iizuka H
    Expression of human cystatin A by keratinocytes is positively regulated via the Ras/MEKK1/MKK7/JNK signal transduction pathway but negatively regulated via the Ras/Raf-1/MEK1/ERK pathway. The Journal of biological chemistry 2001 Sep 28;276(39):36632-8
  19. Sayama K, Hanakawa Y, Shirakata Y, Yamasaki K, Sawada Y, Sun L, Yamanishi K, Ichijo H, Hashimoto K
    Apoptosis signal-regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation. The Journal of biological chemistry 2001 Jan 12;276(2):999-1004
  20. Västrik I, Kaipainen A, Penttilä TL, Lymboussakis A, Alitalo R, Parvinen M, Alitalo K
    Expression of the mad gene during cell differentiation in vivo and its inhibition of cell growth in vitro. The Journal of cell biology 1995 Mar;128(6):1197-208
  21. Descargues P, Sil AK, Sano Y, Korchynskyi O, Han G, Owens P, Wang XJ, Karin M
    IKKalpha is a critical coregulator of a Smad4-independent TGFbeta-Smad2/3 signaling pathway that controls keratinocyte differentiation. Proceedings of the National Academy of Sciences of the United States of America 2008 Feb 19;105(7):2487-92
  22. Lefort K, Dotto GP
    Notch signaling in the integrated control of keratinocyte growth/differentiation and tumor suppression. Seminars in cancer biology 2004 Oct;14(5):374-86
  23. Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, Aster JC, Krishna S, Metzger D, Chambon P, Miele L, Aguet M, Radtke F, Dotto GP
    Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. The EMBO journal 2001 Jul 2;20(13):3427-36

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