Surfactant metabolism (Homo sapiens)

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1, 15, 16, 24, 36...32, 4, 12, 52, 58...23, 30, 45, 5911, 62, 6437, 42, 46, 6728, 10, 39, 6823, 30, 45, 5920, 25, 34, 63, 6521, 3511, 6211, 646, 14, 18, 22, 31...7, 47, 48338, 10, 28, 3926, 385, 56, 623611, 625513, 17, 19327, 29, 32, 43, 44, 54289, 40, 49, 66cytosolmultivesicular bodyendoplasmic reticulum lumenlamellar bodyTYPE II ALVEOLAR CELLclathrin-coated endocytic vesiclenucleoplasmcytosolALVEOLAR MACROPHAGESFTPAsH2OLMCD1 ADRA2C H2OCCDC59 SFTA3 PC SFTPB pro-SFTPCpro-SFTPB,CPALM-C100-CKAP4:SFTPAsSFTPA1 SFTPA2 P2RY2 SFTPC gene PALM-C100-CKAP4 ADPSLC34A1,2PALM-C100-CKAP4 ATP PGA4 ADORA2A,B:Ade-RibCCDC59:TTF1CCDC59ADORA2A,BSFTPD SFTPCCSF2RB GATA6 NAd SFTA3 pro-SFTPCCSF2RA:CSF2RBSFTPB(201-279) PALM-C100-CKAP4Na+SFTPB gene SFTPD SFTPD 12merCTSH(98-105) LMCD1:GATA6SFTPD P2RY2:ATPGATA6ADR GPR116PC, PGHPO4(2-)SFTPB CSF2RA:CSF2RB:SFTPsSFTPB dimerSFTPAsTTF1 DMBT1 SLC34A2 SFTPB dimerInoSFTPA1 TTF1SFTPB(201-279)SFTPAspro-SFTPBCCDC59 Zn2+ SFTPCSFTPB(280-381)CECR1 SFTPC(59-197)CECR1:Zn2+ dimerpro-SFTPB SFTA3 gene CKAP4SFTPA1 gene CSF2RA SFTPA2 Na+SFTPA2 SFTPD PC SFTA3 H2OPC SFTPC(24-58)CSF2RB SFTPB ATPSFTPA2 ADORA2A PALM-CoASFTPCPC, PGADORA2B SFTA3 CTSH(116-292) SFTPB(25-200)CSF2RA SLC34A1 SFTPA2 SFTPD 12mer, SFTPAsDMBT1:SFTPD 12mer,SFTPAsCCDC59:TTF1:SFTPCgeneSFTPD Ade-Rib SFTPA1 NH3SFTA3 GATA6 Ade-RibCTSH(293-335) CCDC59 PiPGA3 SFTPAs ADORA2A NAPSA SFTPA1 SFTPD 12merH2OSFTPD geneADRA2A,C:ADR,NAdSFTPB dimerPG SFTPA genesGATA6:SFTPAsNAPSA, CTSH, PGA3-5SFTPA2 gene SFTPA2 gene ZDHHC2HPO4(2-)TTF1 SFTPB CoA-SHpro-SFTPBSFTPB geneSFTPC geneADORA2B LMCD1SFTPA1 gene PG SFTPA1 SFTA3 gene ABCA3SFTPC SFTPA1 CCDC59:TTF1:SFTPBgenepro-SFTPC DMBT1PC, PGSFTPA2 PGA5 SFTPD 12merPALM-C100-CKAP4:SFTPAsSFTPAs TTF1 SFTPD PG SFTPB dimerADRA2A SFTA3


Description

The alveolar region of the lung creates an extensive epithelial surface that mediates the transfer of oxygen and carbon dioxide required for respiration after birth. Type I epithelial cells form the alveolar surface and mediate gaseous exchange. Type II epithelial cells secrete pulmonary surfactant, a lipoprotein complex that forms a thin interfacial film, lowering surface tension at the air-liquid interface in alveoli and maintaining the structural integrity of alveoli, preventing their collapse at low volumes. Surfactant production is increased prior to birth, in preparation for air breathing at birth (Hallman 2013). Pre-term infants, where type II epithelial cells are not fully differentiated yet, can produce insufficient surfactant and result in respiratory distress syndrome. Surfactant is composed primarily of phospholipids enriched in phosphatidylcholine (PC) and phosphatidylglycerol (PG) (Agassandian & Mallampalli 2013) and the pulmonary collectins, termed surfactant proteins A, B, C and D (SFTPA-D). They influence surfactant homeostasis, contributing to the physical structures of lipids in the alveoli and to the regulation of surfactant function and metabolism. They are directly secreted from alveolar type II cells into the airway to function as part of the surfactant. SFTPA and D are large, hydrophilic proteins while SFTPB and C are small, very hydrophobic proteins (Johansson et al. 1994). In addition to their surfactant functions, SFTPA and D play important roles in innate host defense by binding and clearing invading microbes from the lung (Kingma & Whitsett 2006). Nuclear regulation, transport, metabolism, reutilisation and degradation of surfactant are described here (Ikegami 2006, Boggaram 2009, Whitsett et al. 2010). Mutations in genes involved in these processes can result in respiratory distress syndrome, lung proteinosis, interstitial lung diseases and chronic lung diseases (Perez-Gil & Weaver 2010, Whitsett et al. 2010, Akella & Deshpande 2013, Jo 2014). View original pathway at:Reactome.

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Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
115028view16:56, 25 January 2021ReactomeTeamReactome version 75
113473view11:55, 2 November 2020ReactomeTeamReactome version 74
112672view16:06, 9 October 2020ReactomeTeamReactome version 73
101589view11:45, 1 November 2018ReactomeTeamreactome version 66
101125view21:30, 31 October 2018ReactomeTeamreactome version 65
100653view20:03, 31 October 2018ReactomeTeamreactome version 64
100203view16:48, 31 October 2018ReactomeTeamreactome version 63
99754view15:14, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93821view13:38, 16 August 2017ReactomeTeamreactome version 61
93369view11:21, 9 August 2017ReactomeTeamreactome version 61
87146view18:54, 18 July 2016EgonwOntology Term : 'classic metabolic pathway' added !
87145view18:53, 18 July 2016EgonwOntology Term : 'PW:0000423' removed !
87143view18:53, 18 July 2016EgonwOntology Term : 'surfactant homeostasis pathway' added !
86454view09:18, 11 July 2016ReactomeTeamreactome version 56
83469view12:32, 18 November 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ABCA3ProteinQ99758 (Uniprot-TrEMBL)
ADORA2A ProteinP29274 (Uniprot-TrEMBL)
ADORA2A,B:Ade-RibComplexR-HSA-418926 (Reactome)
ADORA2A,BComplexR-HSA-418907 (Reactome)
ADORA2B ProteinP29275 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ADR MetaboliteCHEBI:28918 (ChEBI)
ADRA2A ProteinP08913 (Uniprot-TrEMBL)
ADRA2A,C:ADR,NAdComplexR-HSA-400090 (Reactome)
ADRA2C ProteinP18825 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ade-Rib MetaboliteCHEBI:16335 (ChEBI)
Ade-RibMetaboliteCHEBI:16335 (ChEBI)
CCDC59 ProteinQ9P031 (Uniprot-TrEMBL)
CCDC59:TTF1:SFTPB geneComplexR-HSA-5685200 (Reactome)
CCDC59:TTF1:SFTPC geneComplexR-HSA-5685207 (Reactome)
CCDC59:TTF1ComplexR-HSA-5683820 (Reactome)
CCDC59ProteinQ9P031 (Uniprot-TrEMBL)
CECR1 ProteinQ9NZK5 (Uniprot-TrEMBL)
CECR1:Zn2+ dimerComplexR-HSA-5693363 (Reactome)
CKAP4ProteinQ07065 (Uniprot-TrEMBL)
CSF2RA ProteinP15509 (Uniprot-TrEMBL)
CSF2RA:CSF2RB:SFTPsComplexR-HSA-5686345 (Reactome)
CSF2RA:CSF2RBComplexR-HSA-5686355 (Reactome)
CSF2RB ProteinP32927 (Uniprot-TrEMBL)
CTSH(116-292) ProteinP09668 (Uniprot-TrEMBL)
CTSH(293-335) ProteinP09668 (Uniprot-TrEMBL)
CTSH(98-105) ProteinP09668 (Uniprot-TrEMBL)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DMBT1 ProteinQ9UGM3 (Uniprot-TrEMBL)
DMBT1:SFTPD 12mer, SFTPAsComplexR-HSA-5687299 (Reactome)
DMBT1ProteinQ9UGM3 (Uniprot-TrEMBL)
GATA6 ProteinQ92908 (Uniprot-TrEMBL)
GATA6:SFTPAsComplexR-HSA-5685293 (Reactome)
GATA6ProteinQ92908 (Uniprot-TrEMBL)
GPR116ProteinQ8IZF2 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
HPO4(2-)MetaboliteCHEBI:43474 (ChEBI)
InoMetaboliteCHEBI:17596 (ChEBI)
LMCD1 ProteinQ9NZU5 (Uniprot-TrEMBL)
LMCD1:GATA6ComplexR-HSA-5683868 (Reactome)
LMCD1ProteinQ9NZU5 (Uniprot-TrEMBL)
NAPSA ProteinO96009 (Uniprot-TrEMBL)
NAPSA, CTSH, PGA3-5ComplexR-HSA-5685893 (Reactome)
NAd MetaboliteCHEBI:18357 (ChEBI)
NH3MetaboliteCHEBI:16134 (ChEBI)
Na+MetaboliteCHEBI:29101 (ChEBI)
P2RY2 ProteinP41231 (Uniprot-TrEMBL)
P2RY2:ATPComplexR-HSA-417866 (Reactome)
PALM-C100-CKAP4 ProteinQ07065 (Uniprot-TrEMBL)
PALM-C100-CKAP4:SFTPAsComplexR-HSA-5686276 (Reactome)
PALM-C100-CKAP4:SFTPAsComplexR-HSA-5686288 (Reactome)
PALM-C100-CKAP4ProteinQ07065 (Uniprot-TrEMBL)
PALM-CoAMetaboliteCHEBI:15525 (ChEBI)
PC MetaboliteCHEBI:16110 (ChEBI)
PC, PGComplexR-HSA-R-ALL-5684863 (Reactome)
PC, PGComplexR-HSA-R-ALL-5684869 (Reactome)
PC, PGComplexR-HSA-R-ALL-5686242 (Reactome)
PG MetaboliteCHEBI:17517 (ChEBI)
PGA3 ProteinP0DJD8 (Uniprot-TrEMBL)
PGA4 ProteinP0DJD7 (Uniprot-TrEMBL)
PGA5 ProteinP0DJD9 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
SFTA3 ProteinP0C7M3 (Uniprot-TrEMBL)
SFTA3 gene ProteinENSG00000229415 (Ensembl)
SFTPA genesComplexR-HSA-5683869 (Reactome)
SFTPA1 ProteinQ8IWL2 (Uniprot-TrEMBL)
SFTPA1 gene ProteinENSG00000122852 (Ensembl)
SFTPA2 ProteinQ8IWL1 (Uniprot-TrEMBL)
SFTPA2 gene ProteinENSG00000185303 (Ensembl)
SFTPAs R-HSA-5685647 (Reactome)
SFTPAsComplexR-HSA-5683863 (Reactome)
SFTPAsComplexR-HSA-5685647 (Reactome)
SFTPAsComplexR-HSA-5686362 (Reactome)
SFTPB ProteinP07988 (Uniprot-TrEMBL)
SFTPB dimerComplexR-HSA-6791014 (Reactome)
SFTPB dimerComplexR-HSA-6791019 (Reactome)
SFTPB dimerComplexR-HSA-6792856 (Reactome)
SFTPB dimerComplexR-HSA-6792858 (Reactome)
SFTPB gene ProteinENSG00000168878 (Ensembl)
SFTPB geneGeneProductENSG00000168878 (Ensembl)
SFTPB(201-279) ProteinP07988 (Uniprot-TrEMBL)
SFTPB(201-279)ProteinP07988 (Uniprot-TrEMBL)
SFTPB(25-200)ProteinP07988 (Uniprot-TrEMBL)
SFTPB(280-381)ProteinP07988 (Uniprot-TrEMBL)
SFTPC ProteinP11686 (Uniprot-TrEMBL)
SFTPC gene ProteinENSG00000168484 (Ensembl)
SFTPC geneGeneProductENSG00000168484 (Ensembl)
SFTPC(24-58)ProteinP11686 (Uniprot-TrEMBL)
SFTPC(59-197)ProteinP11686 (Uniprot-TrEMBL)
SFTPCProteinP11686 (Uniprot-TrEMBL)
SFTPD 12mer, SFTPAsComplexR-HSA-5687334 (Reactome)
SFTPD 12merComplexR-HSA-5685919 (Reactome)
SFTPD 12merComplexR-HSA-5686241 (Reactome)
SFTPD 12merComplexR-HSA-5686361 (Reactome)
SFTPD ProteinP35247 (Uniprot-TrEMBL)
SFTPD geneGeneProductENSG00000133661 (Ensembl)
SLC34A1 ProteinQ06495 (Uniprot-TrEMBL)
SLC34A1,2ComplexR-HSA-427640 (Reactome)
SLC34A2 ProteinO95436 (Uniprot-TrEMBL)
TTF1 ProteinQ15361 (Uniprot-TrEMBL)
TTF1ProteinQ15361 (Uniprot-TrEMBL)
ZDHHC2ProteinQ9UIJ5 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
pro-SFTPB ProteinP07988 (Uniprot-TrEMBL)
pro-SFTPB,CComplexR-HSA-5685626 (Reactome)
pro-SFTPBProteinP07988 (Uniprot-TrEMBL)
pro-SFTPC ProteinP11686 (Uniprot-TrEMBL)
pro-SFTPCProteinP11686 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ABCA3mim-catalysisR-HSA-5683714 (Reactome)
ADORA2A,B:Ade-RibArrowR-HSA-418925 (Reactome)
ADORA2A,B:Ade-RibArrowR-HSA-5684862 (Reactome)
ADORA2A,BR-HSA-418925 (Reactome)
ADPArrowR-HSA-5683714 (Reactome)
ADRA2A,C:ADR,NAdArrowR-HSA-5684862 (Reactome)
ATPR-HSA-5683714 (Reactome)
Ade-RibR-HSA-418925 (Reactome)
Ade-RibR-HSA-5693346 (Reactome)
CCDC59:TTF1:SFTPB geneArrowR-HSA-5685208 (Reactome)
CCDC59:TTF1:SFTPB geneR-HSA-5683840 (Reactome)
CCDC59:TTF1:SFTPC geneArrowR-HSA-5685201 (Reactome)
CCDC59:TTF1:SFTPC geneR-HSA-5683836 (Reactome)
CCDC59:TTF1ArrowR-HSA-5683831 (Reactome)
CCDC59:TTF1R-HSA-5685201 (Reactome)
CCDC59:TTF1R-HSA-5685208 (Reactome)
CCDC59R-HSA-5683831 (Reactome)
CECR1:Zn2+ dimermim-catalysisR-HSA-5693346 (Reactome)
CKAP4R-HSA-5686304 (Reactome)
CSF2RA:CSF2RB:SFTPsArrowR-HSA-5686335 (Reactome)
CSF2RA:CSF2RB:SFTPsR-HSA-5686359 (Reactome)
CSF2RA:CSF2RBArrowR-HSA-5686359 (Reactome)
CSF2RA:CSF2RBR-HSA-5686335 (Reactome)
CoA-SHArrowR-HSA-5686304 (Reactome)
DMBT1:SFTPD 12mer, SFTPAsArrowR-HSA-5687284 (Reactome)
DMBT1R-HSA-5687284 (Reactome)
GATA6:SFTPAsArrowR-HSA-5685296 (Reactome)
GATA6:SFTPAsR-HSA-5683879 (Reactome)
GATA6R-HSA-5683888 (Reactome)
GATA6R-HSA-5685296 (Reactome)
GPR116TBarR-HSA-5684862 (Reactome)
H2OR-HSA-5683714 (Reactome)
H2OR-HSA-5684864 (Reactome)
H2OR-HSA-5685902 (Reactome)
H2OR-HSA-5693346 (Reactome)
HPO4(2-)ArrowR-HSA-427656 (Reactome)
HPO4(2-)R-HSA-427656 (Reactome)
InoArrowR-HSA-5693346 (Reactome)
LMCD1:GATA6ArrowR-HSA-5683888 (Reactome)
LMCD1R-HSA-5683888 (Reactome)
NAPSA, CTSH, PGA3-5mim-catalysisR-HSA-5684864 (Reactome)
NAPSA, CTSH, PGA3-5mim-catalysisR-HSA-5685902 (Reactome)
NH3ArrowR-HSA-5693346 (Reactome)
Na+ArrowR-HSA-427656 (Reactome)
Na+R-HSA-427656 (Reactome)
P2RY2:ATPArrowR-HSA-5684862 (Reactome)
PALM-C100-CKAP4:SFTPAsArrowR-HSA-5686286 (Reactome)
PALM-C100-CKAP4:SFTPAsArrowR-HSA-5686301 (Reactome)
PALM-C100-CKAP4:SFTPAsR-HSA-5686286 (Reactome)
PALM-C100-CKAP4ArrowR-HSA-5686304 (Reactome)
PALM-C100-CKAP4R-HSA-5686301 (Reactome)
PALM-CoAR-HSA-5686304 (Reactome)
PC, PGArrowR-HSA-5683714 (Reactome)
PC, PGArrowR-HSA-5684862 (Reactome)
PC, PGR-HSA-5683714 (Reactome)
PC, PGR-HSA-5684862 (Reactome)
PiArrowR-HSA-5683714 (Reactome)
R-HSA-418925 (Reactome) Adenosine receptors A2a and A2b (ADORA2A and ADORA2B) bind extracellular adenosine (Ado-Rib) and are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow (Peterfreund 1996). The A2A receptor is responsible for regulating myocardial blood flow by vasodilation of the coronary arteries, which increases blood flow to the myocardium, but may lead to hypotension. Just as in A1 receptors, this normally serves as a protective mechanism. A2B receptor work (Pierce KD et al, 1992) has lagged behind research in the other adenosine receptors.
Both ADORA receptors mediate their actions by coupling with the G protein alpha s subunit which activates adenylyl cyclase and increases intracellular cAMP concentrations. In surfactant physiology, the receptor:adenosine complex positively regulates surfactant export from lamellar bodies. (Cooper JA et al, 1995; Linden J et al, 1999). Adenosine deaminase (CECR1, ADA2) degrades extracellular adenosine (Ade-Rib), reducing or neutralising the positive regulatory effect of adenosine in surfactant export.
R-HSA-427656 (Reactome) SLC34A1 encodes Na+/Pi cotransporter (NaPi-IIa) which is expressed in the kidney in the renal proximal tubule (Magagnin et al. 1993). SLC34A2 encodes NaPi-IIb which is abundantly expressed in lung and to a lesser degree in tissues of epithelial origin including small intestine, pancreas, prostate, and kidney (Field et al. 1999). In the lung, SLC34A2 is expressed only in alveolar type II cells, which are responsible for surfactant production, so it is proposed that it uptakes liberated phosphate from the alveolar fluid for surfactant production. Both NaPi-IIa and NaPi-IIb cotransport divalent phosphate (HPO4(2-)) with three Na+ ions (electrogenic transport) (Forster et al. 1999, 2002).

Defects in SLC34A1 are the cause of hypophosphatemic nephrolithiasis/osteoporosis type 1 (NPHLOP1) (Prie et al. 2002). Defects in SLC34A2 are a cause of pulmonary alveolar microlithiasis, a rare disease characterised by the deposition of calcium phosphate microliths throughout the lung (Corut et al. 2006).
R-HSA-5683714 (Reactome) ATP-binding cassette sub-family A member 3 (ABCA3) plays an important role in the formation of pulmonary surfactant, probably by transporting phospholipids such as phosphatidylcholine (PC) and phosphatidylglycerol (PG) from the ER membrane to lamellar bodies (LBs). PC and PG are the major phospholipid constituents of pulmonary surfactant. LBs are the surfactant storage organelles of type II epithelial cells from where phospholipids can be secreted together with surfactant proteins (SFTPs) into the alveolar airspace (Klugbauer & Hofmann 1996, Yamano et al. 2001). Defects in ABCA3 are the cause of pulmonary surfactant metabolism dysfunction type 3 (SMDP3; MIM:610921) (Shulenin et al. 2004).
R-HSA-5683831 (Reactome) Surfactant proteins B and C (SFTPB and C) are small hydrophobic surfactant proteins that maintain surface tension in alveoli. Both SFTPB and C are regulated by a key factor, transcription termination factor 1 (TTF1), in lung cells (Evers & Grummt 1995). Thyroid transcription factor 1-associated protein 26 (CCDC59 aka TAP26, BR22) (Yang et al. 2003) binds to TTF1 and enhances TTF1-transactivated SFTPB and C promoter activity (Yang et al. 2006).
R-HSA-5683836 (Reactome) The human gene SFTPC, bound to the transcription complex transcription termination factor 1 and thyroid transcription factor 1-associated protein 26 (TTF1:CCDC59), enhances TTF1-transactivated SFTPC promoter activity to produce surfactant protein C (SFTPC) (Whitsett & Glasser 1998, Kelly et al. 1996).
R-HSA-5683840 (Reactome) The human gene SFTPB, bound to the transcription complex transcription termination factor 1 and thyroid transcription factor 1-associated protein 26 (TTF1:CCDC59), enhances TTF1-transactivated SFTPB promoter activity to produce surfactant protein B (SFTPB) (Whitsett & Glasser 1998, Yang et al. 2006).
R-HSA-5683879 (Reactome) Human SFTPA1, 2 and 3 produces the equivalent pulmonary surfactant-associated proteins A1, A2 and A3. Their function is to bind surfactant phospholipids and contribute to lowering the surface tension at the air-liquid interface in the alveoli (White et al. 1985, Flores et al. 1986, Schicht et al. 2014). Surfactant proteins A and D function as innate immunity molecules and inflammatory mediators in the lung (Silveyra & Floros 2013). Transcription factor GATA-6 (GATA6) can bind to a cis-acting element in the surfactant protein A (SFTPA) gene promoter, activating the transcriptional activity of the gene (Bruno et al. 2000). The final processed products for SFTPA1 and 2 are six sets of trimers (Haagsman et al. 1989).
R-HSA-5683888 (Reactome) The GATA transcription factors regulate gene expression in a variety of cell types including cardiovascular, pulmonary and hematopoietic tissues. LIM and cysteine-rich domains protein 1 (LMCD1) is a transcriptional cofactor that binds GATA6 and thus restricts its function by inhibiting its DNA-binding, resulting in repression of GATA6 transcriptional activation of downstream target genes (Rath et al. 2005).
R-HSA-5684862 (Reactome) Surfactant-containing lamellar bodies (LBs) are secreted from alveolar type II cells. Regulation of this secretion process is mediated by three G protein-coupled receptor (GPCR)-mediated pathways; P2RY2 purinoreceptor pathway (Rice & Singleton 1986), beta2 adrenergic receptor (beta2AR) pathway (Dobbs & Mason 1979) and adenosine A2B pathway (Gilfillan & Rooney 1987). Activation of these GPCR pathways cause increases in second messengers, such as adenosine 3',5'-cyclic monophosphate (cAMP) or cytosolic Ca2+, and stimulation of downstream kinases such as protein kinase C that leads to surfactant secretion (Voyno-Yasenetskaya et al. 1991). The orphan receptor GPR116 can negatively mediate this secretory process as well as having a stimulatory effect on surfactant reuptake. Gpr116-deficient mice were found to have excessive secretion and accumulation of surfactant in their airspaces after birth (Yang et al. 2013, Bridges et al. 2013, Fukuzawa et al. 2013, Liebscher et al. 2014).
R-HSA-5684864 (Reactome) In the multivesicular body, surfactant precursor protein pro-SFTPB is most likely proteolytically cleaved by napsin-A (NAPSA), cathepsin-H (CTSH) and pepsinogens 3-5 (PGA3-5) (Chuman et al. 1999, Fuchs & Gassen 1989, Athauda et al. 1989, Johansson et al. 1992). The resultant mature peptide SFTPB (chain 201-279) forms a dimeric, disulfide-linked protein (Johansson et al. 1992) and is trafficked to lamellar bodies.
R-HSA-5684865 (Reactome) The mature surfactant proteins B dimer and C (SFTPB dimer and C) are translocated to lamellar bodies (LBs), ready for secretion (Whitsett et al. 2010). The mechanism of transport is unknown.
R-HSA-5684868 (Reactome) Surfactant proteins (SFTPs) are trafficked from the ER membrane to lamellar bodies (LBs) via the multi-vesicle body (MVB). The pro-SFTPs B and C are cleaved here to produce functional SFTPs (Voorhout et al. 1992, Weaver et al. 1992, Conkright et al. 2001).
R-HSA-5685201 (Reactome) Surfactant protein C (SFTPC) is a small hydrophobic surfactant protein that maintains surface tension in alveoli. In the nucleus, SFTPC is regulated by a key factor, transcription termination factor 1 (TTF1), bound to thyroid transcription factor 1-associated protein 26 (CCDC59 aka TAP26, BR22), to enhance TTF1-transactivated SFTPC promoter activity (Kelly et al. 1996, Whitsett & Glasser 1998, Yang et al. 2006).
R-HSA-5685208 (Reactome) Surfactant proteins B (SFTPB) is a small hydrophobic surfactant protein that maintains surface tension in alveoli. In the nucleus, SFTPB is regulated by a key factor, transcription termination factor 1 (TTF1), bound to thyroid transcription factor 1-associated protein 26 (CCDC59 aka TAP26, BR22), to enhance TTF1-transactivated SFTPB promoter activity (Whitsett & Glasser 1998, Yang et al. 2006).
R-HSA-5685290 (Reactome) The human gene SFTPD produces pulmonary surfactant-associated protein D. The final processed product is a 12mer consisting of four sets of SFTPD trimer (Rust et al. 1991, Lu et al. 1992, Hakansson et al. 1999). It is secreted into the pulmonary alveoli. In addition to its surfactant-related functions, SFTPD, like SFTPA, contributes to the lung's defense against inhaled pathogens and allergens by binding and clearing these entities from the lung (Lu et al. 1992, Crouch et al. 1993) (not annotated here).
R-HSA-5685296 (Reactome) Transcription factor GATA-6 (GATA6) binds to a cis-acting element in the surfactant protein A1-3 (SFTPAs) gene promoters, activating the transcription of the genes (Bruno et al. 2000).
R-HSA-5685649 (Reactome) The pulmonary collectins, surfactant proteins A1, A2, A3 and D (SFTPAs, D), play important roles in innate host defense by binding and clearing invading microbes from the lung. They also influence surfactant homeostasis, contributing to the physical structures of lipids in the alveoli and to the regulation of surfactant function and metabolism. They are directly secreted from alveolar type II cells into the airway to function as part of the surfactant. The mechanism of secretion is unknown. Mutations in SFTPA2 disrupt protein structure and the defective protein is retained in the ER membrane (thus not secreted). Lack of SFTPA2 in surfactant contributes towards idiopathic pulmonary fibrosis (IPF; MIM:178500) (Wang et al. 2009). The mechanism of pathophysiology is unknown.
R-HSA-5685902 (Reactome) In the multivesicular body, surfactant precursor protein pro-SFTPC is most likely proteolytically cleaved by napsin-A (NAPSA), cathepsin-H (CTSH) and pepsinogens 3-5 (PGA3-5) (Chuman et al. 1999, Fuchs & Gassen 1989, Athauda et al. 1989, Johansson et al. 1988). The resultant mature peptide SFTPC (chain 24-58) is trafficked to lamellar bodies.
R-HSA-5686286 (Reactome) Alveolar surfactant is cleared by distinct pathways. Surfactant proteins (SFTPs) are reutilised by type II cells that internalise alveolar phospholipids destined for re-incorporation into LB for secretion or intra-alveolar or extracellular surfactant is degraded. A substantial portion of surfactant is reutilised (25-95%) in type II cells, promoted by SFTPA (the most abundant surfactant protein) via interaction with a high-affinity receptor present on the cell surface. A candidate for the SFTPA receptor detected on type II epithelial cells is cytoskeleton-associated protein 4 (CKAP4 aka p63), a reversibly palmitoylated transmembrane protein (PALM-C100-CKAP4), initially identified in the ER and Golgi apparatus (Bates 2010). SFTPA and CKAP4 seem to enter the cell as a unit since both are found in early endosomes. At what point SFTPA and CKAP4 separate or whether CKAP4 chaperones SFTPA to the lamellar body is currently unknown. The receptors for the other surfactant proteins (SFTPB, C, D) that are also recycled are not yet identified.
R-HSA-5686301 (Reactome) Alveolar surfactant is cleared by distinct pathways. Surfactant proteins (SFTPs) are reutilised by type II cells that internalise alveolar phospholipids destined for re-incorporation into LB for secretion. Alternatively, intra-alveolar or extracellular surfactant is degraded. A substantial portion of surfactant is reutilised (25-95%) in type II cells, promoted by SFTPA (the most abundant surfactant protein) via interaction with a high-affinity receptor present on the cell surface. A candidate for the SFTPA receptor detected on type II epithelial cells is cytoskeleton-associated protein 4 (CKAP4 aka p63), a reversibly palmitoylated transmembrane protein (PALM-C100-CKAP4), initially identified in the ER and Golgi apparatus (Bates 2010).
R-HSA-5686304 (Reactome) The palmitoyltransferase ZDHHC2 transfers a palmitoyl group (PALM) from the high energy donor palmitoyl-CoA (PALM-CoA) to cytoskeleton-associated protein 4 (CKAP4 aka p63). CKAP4 is thought to be a surfactant A binding protein on the surface of alveolar type II epithelial cells where it plays a role in bridging the plasma membrane to the cytoskeleton and in the reuptake of surfactant A. CKAP4 palmitoylation on the cysteine 100 residue by DHHC2 is required for its trafficking from the ER to the plasma membrane (Schweizer et al. 1993, Planey et al. 2009).
R-HSA-5686335 (Reactome) Surfactant catabolism by alveolar macrophages plays a small but critical part in surfactant recycling and metabolism. Upon ligand binding, granulocyte-macrophage colony-stimulating factor receptor (GM-CSF), a heterodimer of alpha (CSF2RA) and beta (CSF2RB) subunits (Hansen et al. 2008), initiates a signalling process that not only induces proliferation, differentiation and functional activation of hematopoietic cells but can also determine surfactant uptake into alveolar macrophages and its degradation via clathrin-coated vesicles. The exact mechanism of surfactant degradation in macrophages is poorly understood (Jain et al. 2005, Ikegami 2006). GM-CSF-deficiency can result in pulmonary alveolar proteinosis (PAP), a lung disease characterised by surfactant accumulation and lipid-engorged alveolar macrophages (Carey & Trapnell 2010).
R-HSA-5686359 (Reactome) Surfactant catabolism by alveolar macrophages plays a small but critical part in surfactant recycling and metabolism. Upon ligand binding, granulocyte-macrophage colony-stimulating factor receptor (GM-CSF), a heterodimer of alpha (CSF2RA) and beta (CSF2RB) subunits (Hansen et al. 2008), initiates a signalling process that not only induces proliferation, differentiation and functional activation of hematopoietic cells but can also determine surfactant uptake into alveolar macrophages and its degradation via clathrin-coated vesicles. The exact mechanism of surfactant degradation in macrophages is poorly understood (Jain et al. 2005, Ikegami 2006). GM-CSF-deficiency can result in pulmonary alveolar proteinosis (PAP), a lung disease characterised by surfactant accumulation and lipid-engorged alveolar macrophages (Carey & Trapnell 2010).
R-HSA-5687284 (Reactome) Deleted in malignant brain tumors 1 protein (DMBT1 aka Gp-340, Hensin, salivary agglutinin) is a binding protein that could play a role in mucosal innate immunity. It is secreted into the broncho-alveolar surface lining fluid and in saliva. DMTB1 can bind surfactant proteins SFTPA and D in macrophage tissues, the resulting complex being able to interact with and agglutinate several Gram-negative and Gram-positive bacteria (Holmskov et al. 1999, Ligtenberg et al. 2001; reviews - Lightenberg et al. 2007, Madsen et al. 2010). DMBT1 has been proposed as a tumor suppressor gene candidate in human brain tumors. Two mutations, one of which resulted in an amino acid change (Q420H), occurred in glioblastomas (Mueller et al. 2002).
R-HSA-5693346 (Reactome) Adenosine deaminase (CECR1, ADA2) degrades extracellular adenosine (Ade-Rib), a signaling molecule that controls a variety of cellular responses (Zavialov & Engstrom 2005). Extracellular adenosine can bind and activate four adenosine receptors (ADRs), triggering multiple intracellular processes leading to either cell activation or in suppression of cell function and cell death. ADA2 (and ADA1) decrease the local concentration of adenosine by catalysing the deamination of adenosine to inosine (Ino). ADA2 is dimeric, binding one Zn2+ ion per subunit (Zavialov et al. 2010).
R-HSA-6791016 (Reactome) After pro-SFTPB is cleaved, the resultant mature peptide SFTPB (chain 201-279) forms a dimeric, disulfide linked protein (Johansson et al. 1992) and is trafficked to lamellar bodies.
SFTPA genesR-HSA-5685296 (Reactome)
SFTPAsArrowR-HSA-5683879 (Reactome)
SFTPAsArrowR-HSA-5685649 (Reactome)
SFTPAsArrowR-HSA-5686359 (Reactome)
SFTPAsR-HSA-5685649 (Reactome)
SFTPAsR-HSA-5686301 (Reactome)
SFTPAsR-HSA-5686335 (Reactome)
SFTPB dimerArrowR-HSA-5684862 (Reactome)
SFTPB dimerArrowR-HSA-5684865 (Reactome)
SFTPB dimerArrowR-HSA-5686359 (Reactome)
SFTPB dimerArrowR-HSA-6791016 (Reactome)
SFTPB dimerR-HSA-5684862 (Reactome)
SFTPB dimerR-HSA-5684865 (Reactome)
SFTPB dimerR-HSA-5686335 (Reactome)
SFTPB geneR-HSA-5685208 (Reactome)
SFTPB(201-279)ArrowR-HSA-5684864 (Reactome)
SFTPB(201-279)R-HSA-6791016 (Reactome)
SFTPB(25-200)ArrowR-HSA-5684864 (Reactome)
SFTPB(280-381)ArrowR-HSA-5684864 (Reactome)
SFTPC geneR-HSA-5685201 (Reactome)
SFTPC(24-58)ArrowR-HSA-5685902 (Reactome)
SFTPC(24-58)R-HSA-5684865 (Reactome)
SFTPC(59-197)ArrowR-HSA-5685902 (Reactome)
SFTPCArrowR-HSA-5684862 (Reactome)
SFTPCArrowR-HSA-5684865 (Reactome)
SFTPCArrowR-HSA-5686359 (Reactome)
SFTPCR-HSA-5684862 (Reactome)
SFTPCR-HSA-5686335 (Reactome)
SFTPD 12mer, SFTPAsR-HSA-5687284 (Reactome)
SFTPD 12merArrowR-HSA-5685290 (Reactome)
SFTPD 12merArrowR-HSA-5685649 (Reactome)
SFTPD 12merArrowR-HSA-5686359 (Reactome)
SFTPD 12merR-HSA-5685649 (Reactome)
SFTPD 12merR-HSA-5686335 (Reactome)
SFTPD geneR-HSA-5685290 (Reactome)
SLC34A1,2mim-catalysisR-HSA-427656 (Reactome)
TTF1R-HSA-5683831 (Reactome)
ZDHHC2mim-catalysisR-HSA-5686304 (Reactome)
pro-SFTPB,CArrowR-HSA-5684868 (Reactome)
pro-SFTPBArrowR-HSA-5683840 (Reactome)
pro-SFTPBR-HSA-5684864 (Reactome)
pro-SFTPBR-HSA-5684868 (Reactome)
pro-SFTPCArrowR-HSA-5683836 (Reactome)
pro-SFTPCR-HSA-5684868 (Reactome)
pro-SFTPCR-HSA-5685902 (Reactome)
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