KEGG PATHWAY: cel04361

PATHWAY: cel04361

Entry

cel04361                    Pathway

Name

Axon regeneration - Caenorhabditis elegans (nematode)

Description

Many mature central nervous system (CNS) neurons in non-mammals, such as C. elegans, Drosophila, and zebrafish, are able to regenerate after injuries. The MAPK cascade, DLK-1/MKK-4/PMK-3/MAK2, is identified as an essential signaling pathway involved in axon regeneration in C. elegans. Calcium influx, which is triggered by axotomy, is implicated in DLK-1 activation. Another MAP kinase pathway, MLK-1/MEK-1/KGB-1, acts in parallel with the DLK-1 pathway to control growth-cone formation after axotomy. SVH-1, a homolog of the mammalian hepatocyte growth factor and its receptor SVH-2 function upstream of the MLK-1 pathway to promote axon regeneration. There are also inhibitors of regeneration, such as lin-12/Notch and efa-6. It is possible that the C. elegans pathways that inhibit regeneration function to stabilize the mature, uninjured nervous system.

Class

Organismal Systems; Development and regeneration

Pathway map

cel04361

Axon regeneration

Organism

Caenorhabditis elegans (nematode) [GN:cel]

Gene

CELE_C48A7.1

egl-19; Voltage-dependent L-type calcium channel subunit alpha [KO:K04851]

CELE_F17C8.1

acy-1; Guanylate cyclase domain-containing protein [KO:K08049] [EC:4.6.1.1]

CELE_ZK909.2

kin-1; Protein kinase domain-containing protein [KO:K04345] [EC:2.7.11.11]

CELE_C35D10.9

ced-4; Cell death protein 4 [KO:K20105]

CELE_C48D1.2

ced-3; Cell death protein 3 subunit p17 [KO:K20106]

CELE_C01B7.6

rpm-1; E3 ubiquitin-protein ligase rpm-1 [KO:K10693] [EC:2.3.2.33]

CELE_F07B7.12

F07B7.12; PHR domain-containing protein [KO:K10693] [EC:2.3.2.33]

CELE_F33E2.2

dlk-1; Mitogen-activated protein kinase kinase kinase dlk-1 [KO:K04422] [EC:2.7.11.25]

CELE_F42G10.2

mkk-4; MAP kinase kinase mkk-4 [KO:K04430] [EC:2.7.12.2]

CELE_VZC374L.1

sek-6; Protein kinase domain-containing protein [KO:K04430] [EC:2.7.12.2]

CELE_ZC449.3

sek-3; Protein kinase domain-containing protein [KO:K04430] [EC:2.7.12.2]

CELE_F42G8.3

pmk-2; Mitogen-activated protein kinase pmk-2 [KO:K04441] [EC:2.7.11.24]

CELE_B0218.3

pmk-1; Mitogen-activated protein kinase pmk-1 [KO:K04441] [EC:2.7.11.24]

CELE_F42G8.4

pmk-3; Mitogen-activated protein kinase pmk-3 [KO:K04441] [EC:2.7.11.24]

CELE_C44C8.6

mak-2; MAP kinase-activated protein kinase mak-2 [KO:K04443] [EC:2.7.11.1]

CELE_F22A3.1

ets-4; Transcription factor ets-4 [KO:K09442]

CELE_D1005.3

cebp-1; CCAAT/enhancer-binding protein homolog 1 [KO:K23479]

CELE_T14E8.1

svh-2; Tyrosine-protein kinase receptor svh-2 [KO:K05099] [EC:2.7.10.1]

CELE_Y55D9A.1

efa-6; Exchange factor for Arf-6 [KO:K12494]

CELE_K11D9.1

klp-7; Kinesin-like protein [KO:K10393]

CELE_EEED8.6

ccpp-6; Cytosolic carboxypeptidase 6 [KO:K23439] [EC:3.4.17.24]

CELE_F08B1.1

vhp-1; protein-tyrosine-phosphatase [KO:K04459] [EC:3.1.3.16 3.1.3.48]

CELE_C05B10.1

lip-1; Dual specificity protein phosphatase lip-1 [KO:K04459] [EC:3.1.3.16 3.1.3.48]

CELE_C07G1.1

svh-1; Serine protease svh-1 [KO:K23489]

CELE_K11D12.10

mlk-1; Mitogen-activated protein kinase kinase kinase mlk-1 [KO:K04417] [EC:2.7.11.25]

CELE_K08A8.1

mek-1; Dual specificity mitogen-activated protein kinase kinase mek-1 [KO:K04431] [EC:2.7.12.2]

CELE_B0478.1

jnk-1; Stress-activated protein kinase jnk-1 [KO:K04440] [EC:2.7.11.24]

CELE_T07A9.3

kgb-1; GLH-binding kinase 1 [KO:K04440] [EC:2.7.11.24]

CELE_ZC416.4

kgb-2; Stress-activated protein kinase JNK [KO:K04440] [EC:2.7.11.24]

CELE_F29G9.4

fos-1; Transcription factor fos-1 [KO:K09031]

CELE_B0218.1

faah-1; Fatty acid amide hydrolase 1 [KO:K15528] [EC:3.5.1.99]

CELE_Y56A3A.12

faah-4; Monoglyceride lipase faah-4 [KO:K15528] [EC:3.5.1.99]

CELE_Y41C4A.2

faah-6; Amidase domain-containing protein [KO:K15528] [EC:3.5.1.99]

CELE_B0218.2

faah-2; Amidase domain-containing protein [KO:K15528] [EC:3.5.1.99]

CELE_C26C6.2

goa-1; Guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]

CELE_E02C12.5

gpa-3; Guanine nucleotide-binding protein alpha-3 subunit [KO:K04534]

CELE_F38E1.5

gpa-2; Guanine nucleotide-binding protein alpha-2 subunit [KO:K04534]

CELE_M04C7.1

gpa-15; Guanine nucleotide-binding protein alpha-15 subunit [KO:K04534]

CELE_R10H10.5

gpa-7; Guanine nucleotide-binding protein alpha-7 subunit [KO:K04534]

CELE_T19C4.6

gpa-1; Guanine nucleotide-binding protein alpha-1 subunit [KO:K04534]

CELE_M01D7.7

egl-30; G protein subunit alpha q [KO:K04634]

CELE_B0348.4

egl-8; Phosphoinositide phospholipase C [KO:K05858] [EC:3.1.4.11]

CELE_B0545.1

tpa-1; Protein kinase C-like 1 [KO:K06068] [EC:2.7.11.13]

CELE_C09B7.1

ser-7; G-protein coupled receptors family 1 profile domain-containing protein [KO:K04163]

CELE_R06A10.2

gsa-1; Guanine nucleotide-binding protein G(S) subunit alpha [KO:K04632]

CELE_F18G5.3

gpa-12; Guanine nucleotide-binding protein alpha-12 subunit [KO:K04346]

CELE_F13E6.6

rhgf-1; Guanine nucleotide exchange factor [KO:K07532]

CELE_Y51H4A.3

rho-1; Ras-like GTP-binding protein rhoA [KO:K04513]

CELE_K06A1.6

dgk-5; Diacylglycerol kinase [KO:K00901] [EC:2.7.1.107]

CELE_C09E10.2

dgk-1; Diacylglycerol kinase [KO:K00901] [EC:2.7.1.107]

CELE_F54G8.2

dgk-3; putative diacylglycerol kinase 3 [KO:K00901] [EC:2.7.1.107]

CELE_F46H6.2

dgk-2; Diacylglycerol kinase [KO:K00901] [EC:2.7.1.107]

CELE_F42A9.1

dgk-4; Diacylglycerol kinase [KO:K00901] [EC:2.7.1.107]

CELE_F38A6.3

hif-1; Hypoxia-inducible factor 1 [KO:K08268]

CELE_ZK1290.2

tph-1; Biopterin-dependent aromatic amino acid hydroxylase family profile domain-containing protein [KO:K00502] [EC:1.14.16.4]

CELE_C05D2.3

basl-1; Aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]

CELE_C05D2.4

bas-1; Aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]

CELE_Y55D5A.5

daf-2; Insulin-like receptor subunit beta [KO:K04527] [EC:2.7.10.1]

CELE_B0334.8

age-1; Phosphatidylinositol 3-kinase age-1 [KO:K00922] [EC:2.7.1.153]

CELE_B0261.2

let-363; Target of rapamycin homolog [KO:K07203] [EC:2.7.11.1]

CELE_T07A9.6

daf-18; Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase daf-18 [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]

CELE_R13H8.1

daf-16; Forkhead box protein O [KO:K09408]

CELE_F57C7.3

sdn-1; Syndecan [KO:K16336]

CELE_DY3.7

sup-17; Disintegrin and metalloproteinase domain-containing protein 10 homolog [KO:K06704] [EC:3.4.24.81]

CELE_R107.8

lin-12; lin-12/Notch intracellular domain [KO:K02599]

CELE_F35H12.3

sel-12; Presenilin sel-12 [KO:K04505] [EC:3.4.23.-]

CELE_C18E3.8

hop-1; Presenilin hop-1 [KO:K04505] [EC:3.4.23.-]

CELE_ZK524.1

spe-4; Presenilin spe-4 [KO:K04505] [EC:3.4.23.-]

CELE_R04A9.7

R04A9.7; Non-specific serine/threonine protein kinase [KO:K04688] [EC:2.7.11.1]

CELE_Y47D3A.16

rsks-1; Ribosomal protein S6 kinase beta [KO:K04688] [EC:2.7.11.1]

CELE_T01C8.1

aak-2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]

CELE_PAR2.3

aak-1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]

CELE_F40E10.4

slt-1; Slit homolog 1 protein [KO:K06839]

CELE_M03A1.1

vab-1; Ephrin receptor 1 [KO:K05110] [EC:2.7.10.1]

CELE_ZK377.2

sax-3; Protein sax-3 [KO:K06754]

CELE_F41C6.1

unc-6; Netrin unc-6 [KO:K06843]

CELE_Y50D4C.1

unc-34; WH1 domain-containing protein [KO:K23487]

CELE_F10E9.6

mig-10; Abnormal cell migration protein 10 [KO:K23488]

CELE_ZK470.5

nck-1; NCK (Non-Catalytic region of tyrosine Kinase) adaptor protein family [KO:K19862]

CELE_C09G12.8

ced-10; Ras-related protein ced-10 [KO:K04392]

CELE_C35C5.4

mig-2; Ras-related C3 botulinum toxin substrate 1 [KO:K04392]

CELE_K03D3.10

rac-2; Ras-related protein rac-2 [KO:K04392]

CELE_C05G5.6

let-7; microRNA let-7,b [KO:K16980]

CELE_C12C8.3

lin-41; Protein lin-41 [KO:K12035] [EC:2.3.2.27]

CELE_T07D3.7

alg-2; Protein argonaute-2 [KO:K11593]

CELE_R09A1.1

ergo-1; Piwi-like protein ergo-1 [KO:K11593]

CELE_F48F7.1

alg-1; Protein argonaute-2 [KO:K11593]

CELE_W03C9.4

lin-29; C2H2-type domain-containing protein [KO:K23480]

Compound

C00076

Calcium cation

C00078

L-Tryptophan

C00165

Diacylglycerol

C00575

3',5'-Cyclic AMP

C00643

5-Hydroxy-L-tryptophan

C00780

Serotonin

C11695

Anandamide

Reference

PMID:28213159

Authors

Hisamoto N, Matsumoto K

Title

Signal transduction cascades in axon regeneration: insights from C. elegans.

Journal

Curr Opin Genet Dev 44:54-60 (2017)
DOI:10.1016/j.gde.2017.01.010

Reference

PMID:21907582

Authors

Chen L, Chisholm AD

Title

Axon regeneration mechanisms: insights from C. elegans.

Journal

Trends Cell Biol 21:577-84 (2011)
DOI:10.1016/j.tcb.2011.08.003

Reference

PMID:23846598

Authors

Saijilafu, Zhang BY, Zhou FQ

Title

Signaling pathways that regulate axon regeneration.

Journal

Neurosci Bull 29:411-20 (2013)
DOI:10.1007/s12264-013-1357-4

Reference

PMID:22974301

Authors

El Bejjani R, Hammarlund M

Title

Neural regeneration in Caenorhabditis elegans.

Journal

Annu Rev Genet 46:499-513 (2012)
DOI:10.1146/annurev-genet-110711-155550

Reference

PMID:23844582

Authors

Chisholm AD

Title

Cytoskeletal dynamics in Caenorhabditis elegans axon regeneration.

Journal

Annu Rev Cell Dev Biol 29:271-97 (2013)
DOI:10.1146/annurev-cellbio-101512-122311

Reference

PMID:24794753

Authors

Hammarlund M, Jin Y

Title

Axon regeneration in C. elegans.

Journal

Curr Opin Neurobiol 27:199-207 (2014)
DOI:10.1016/j.conb.2014.04.001

Reference

PMID:25792136

Authors

Pastuhov SI, Hisamoto N, Matsumoto K

Title

MAP kinase cascades regulating axon regeneration in C. elegans.

Journal

Proc Jpn Acad Ser B Phys Biol Sci 91:63-75 (2015)
DOI:10.2183/pjab.91.63

Reference

PMID:26484536

Authors

Li C, Hisamoto N, Matsumoto K

Title

Axon Regeneration Is Regulated by Ets-C/EBP Transcription Complexes Generated by Activation of the cAMP/Ca2+ Signaling Pathways.

Journal

PLoS Genet 11:e1005603 (2015)
DOI:10.1371/journal.pgen.1005603

Reference

PMID:26339988

Authors

Chen L, Chuang M, Koorman T, Boxem M, Jin Y, Chisholm AD

Title

Axon injury triggers EFA-6 mediated destabilization of axonal microtubules via TACC and doublecortin like kinase.

Journal

Elife 4:e08695 (2015)
DOI:10.7554/eLife.08695

Reference

PMID:23072806

Authors

Pastuhov SI, Fujiki K, Nix P, Kanao S, Bastiani M, Matsumoto K, Hisamoto N

Title

Endocannabinoid-Goalpha signalling inhibits axon regeneration in Caenorhabditis elegans by antagonizing Gqalpha-PKC-JNK signalling.

Journal

Nat Commun 3:1136 (2012)
DOI:10.1038/ncomms2136

Reference

PMID:24606896

Authors

Belin S, Norsworthy M, He Z

Title

Independent control of aging and axon regeneration.

Journal

Cell Metab 19:354-6 (2014)
DOI:10.1016/j.cmet.2014.02.014

Reference

PMID:24440228

Authors

Byrne AB, Walradt T, Gardner KE, Hubbert A, Reinke V, Hammarlund M

Title

Insulin/IGF1 signaling inhibits age-dependent axon regeneration.

Journal

Neuron 81:561-73 (2014)
DOI:10.1016/j.neuron.2013.11.019

Reference

PMID:22284174

Authors

Po MD, Calarco JA, Zhen M

Title

Releasing the inner inhibition for axon regeneration.

Journal

Neuron 73:207-9 (2012)
DOI:10.1016/j.neuron.2012.01.002

Reference

PMID:22284182

Authors

El Bejjani R, Hammarlund M

Title

Notch signaling inhibits axon regeneration.

Journal

Neuron 73:268-78 (2012)
DOI:10.1016/j.neuron.2011.11.017

Reference

PMID:18296652

Authors

Gabel CV, Antoine F, Chuang CF, Samuel AD, Chang C

Title

Distinct cellular and molecular mechanisms mediate initial axon development and adult-stage axon regeneration in C. elegans.

Journal

Development 135:1129-36 (2008)
DOI:10.1242/dev.013995

Reference

PMID:24431434

Authors

Hubert T, Wu Z, Chisholm AD, Jin Y

Title

S6 kinase inhibits intrinsic axon regeneration capacity via AMP kinase in Caenorhabditis elegans.

Journal

J Neurosci 34:758-63 (2014)
DOI:10.1523/JNEUROSCI.2886-13.2014

Reference

PMID:23599497

Authors

Zou Y, Chiu H, Zinovyeva A, Ambros V, Chuang CF, Chang C

Title

Developmental decline in neuronal regeneration by the progressive change of two intrinsic timers.

Journal

Science 340:372-376 (2013)
DOI:10.1126/science.1231321

Reference

PMID:23599470

Authors

Nix P, Bastiani M

Title

Neuroscience. Heterochronic genes turn back the clock in old neurons.

Journal

Science 340:282-3 (2013)
DOI:10.1126/science.1237921

Related
pathway

cel04150

mTOR signaling pathway

KO pathway

ko04361

LinkDB

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