Phagocytic engulfment

Phagocytic engulfment is the receptor-driven internalization of a large particle (a microbe, an opsonized target, or an apoptotic cell) into a plasma-membrane-derived vacuole, the nascent phagosome. A cell-surface receptor recognizes the particle, either directly (beta-glucan, phosphatidylserine) or through a bound opsonin or bridging ligand (IgG, iC3b, GAS6). Receptor engagement then activates Rho-family GTPases, Rac and Cdc42 for Fc-gamma and apoptotic-cell receptors and RhoA for complement receptor 3. The GTPases drive Arp2/3-dependent actin polymerization that extends pseudopods around the particle. Class I PI3K activity and dynamin are then needed to complete pseudopod extension and close the phagocytic cup. The Rac-to-actin core is shared by animal phagocytes and phagotrophic amoebae. In Dictyostelium, Rac GTPases, the SCAR/WAVE nucleation-promoting factor and the Arp2/3 complex build the phagocytic cup, and PI(3,4,5)P3 forms at the site of engulfment. The receptors differ between lineages. Amoebae recognize bacteria with receptors such as the GPCR fAR1 and the adhesion protein SibA. Animals use the CED-1/Draper/MEGF10 receptor family and its CED-6/GULP adaptor, and the CRK/DOCK180/ELMO Rac GEF (CED-2/CED-5/CED-12 in C. elegans). Vertebrates add opsonin receptors for IgG and complement and lectin receptors such as Dectin-1.

MODULE:phagocytic_engulfmentDRAFTBiological Processmodules/phagocytic_engulfment.yaml
phagocytosis, engulfmentGO:0006911
GO:0006911
phagocytosis, engulfment
The module is grounded in the GO process for internalizing a particle by surrounding it with plasma membrane. Recognition (GO:0006910) is modelled as the first part. Phagosome maturation (GO:0090382) is a separate module.
PMID:25319336
Phagocytosis: receptors, signal integration, and the cytoskeleton.
Receptor diversity and staged actin remodeling (cortical disruption, then polymerization for pseudopod extension, then termination for closure) set the part order of this module.
the actin polymerization that propels pseudopod extension
PMID:15744306
Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans.
The two partially redundant C. elegans engulfment routes share a Rac output. This supports treating receptor classes as alternative entry points into a shared Rho-GTPase/actin core.
two conserved, partially redundant genetic pathways regulate this process
PMID:36897976
Convergence of Ras- and Rac-regulated formin pathways is pivotal for phagosome formation and particle uptake in Dictyostelium.
In Dictyostelium, as in animal phagocytes, Arp2/3 activity downstream of SCAR/WAVE and Rho-family GTPases builds the protruding rim of the phagocytic cup, and loss of SCAR reduces phagocytosis. This supports a eukaryote-wide context for the Rac-to-actin core of the module.
actin assembly at the tips of macroendocytic cups is initiated by the actin-related protein (Arp) 2/3 complex downstream of the SCAR (suppressor of cAMP receptor)/WAVE (Wiskott-Aldrich syndrome protein family verprolin homologs) complex (also known as the WAVE regulatory complex, WRC) activation and Rho family GTPase signaling
PMID:29799847
A G-protein-coupled chemoattractant receptor recognizes lipopolysaccharide for bacterial phagocytosis.
Dictyostelium lacks Fc-gamma and complement receptors and uses its own receptors to recognize bacteria. Receptor classes are therefore modelled as lineage-specific variants feeding a shared core.
as typical phagocytic receptors, such as complement receptors or Fcγ receptors, have not been found in Dictyostelium, it remains mysterious how these cells recognize bacteria
file:modules/fc_gamma_receptor_signaling.yaml
Module: Fc-gamma receptor signaling pathway
The Fc-gamma receptor recognition variant here covers only the engulfment role. MODULE:fc_gamma_receptor_signaling models the full ITAM/SYK/BTK signaling pathway, including the PLC-gamma and inflammatory branches.
file:modules/phagosome_maturation.yaml
Module: Phagosome maturation
Sibling module. The sealed nascent phagosome produced here is the input to phagosome maturation.

Boundary: this module runs from particle recognition to closure of the phagocytic cup. It does not include phagosome maturation (the Rab5-to-Rab7 transition, lysosome fusion, acidification and the NADPH oxidase), which is in MODULE:phagosome_maturation. Also excluded: generation of "eat-me" signals on the target (for example XKR8-mediated phosphatidylserine exposure, GO:0070782), find-me chemotaxis, "don't-eat-me" checkpoints (CD47-SIRPA), and the inflammatory and transcriptional outputs of phagocytic receptors. LC3-associated phagocytosis (RUBCN, NOX2, ATG16L1 WD40 domain) is a related route that has not been modelled here. Taxon scope. The context is Eukaryota because the core that turns receptor signals into a phagocytic cup is shared by animals and phagotrophic amoebae. Dictyostelium needs Rac GTPases (PMID:10825297), the SCAR/WAVE nucleation-promoting factor (PMID:11683394) and the Arp2/3 complex (PMID:11807934, PMID:36897976) to engulf particles, and makes PI(3,4,5)P3 at engulfment sites (PMID:15572406). Each lineage-specific part carries its own taxon context. The Fc-gamma receptor, CR3 and Dectin-1 variants are vertebrate-only. TIMD4, GAS6 and MERTK in the apoptotic-cell variant are vertebrate-only, while the CED-1/Draper/MEGF10 receptor, CED-6/GULP and the Draper-Shark kinase link are bilaterian. The fAR1/SibA variant is shown only in Dictyostelium. Three core annotons have evidence from animals only. (1) The CRK/DOCK180/ELMO Rac GEF. PAINT places DOCK GEF activity at a eukaryote-level node, and Dictyostelium has an ELMO-DockD complex that acts on Rac during motility (PMID:19037099). But the best-studied amoebal ELMO, ElmoA, restrains phagocytosis rather than promoting it (PMID:18854143), and no amoebal CRK ortholog is known. (2) Class I PI3K at cup closure. In Dictyostelium, class I PI3K products appear at engulfment sites, but a loss-of-function phagocytosis defect for pikA/pikB was not found in the literature reviewed here. (3) Dynamin at cup closure. Dictyostelium dynamin A acts on endo-lysosomal membranes and not at the plasma membrane (PMID:9880338), so only mammalian dynamin 2 evidence supports this step. Receptor variants are alternatives (ONE_OR_MORE). A professional phagocyte usually uses several at once, and opsonic and non-opsonic routes can cooperate. The apoptotic-cell variant combines vertebrate receptors (TIMD4, the GAS6-MERTK bridge) with the CED-1/Draper/MEGF10 receptor family, its CED-6/GULP adaptor and the Syk-like kinase Shark. The CED-1/MEGF10 receptor is grounded on PTHR24035, the family PANTHER's own classification and PAINT use (ced-1 and Draper in SF109, MEGF10 in SF136). The UniProt/InterPro cross-references name PTHR24043 and PTHR24052 instead; see projects/PANTHER_FAMILY_ASSIGNMENT_DISCREPANCIES.md. PANTHER also places Dictyostelium SibA in SF109 (PROTEIN DRAPER), and SibA is a seed of the PAINT node PTN009076277 that carries scavenger receptor activity for CED-1 and MEGF10. SibA is nevertheless modelled as a separate amoebal gene product, because its assayed role is adhesion to particles and no ligand-binding activity has been shown. Whether it shares an ancestral engulfment-receptor function with CED-1 is recorded as a knowledge gap. Not modelled as annotons. TM9/Phg1 nonaspanins (Dictyostelium Phg1A, Drosophila TM9SF4) are needed for adhesion to particles and phagocytosis in both lineages (PMID:10944536, PMID:18796536). Phg1A acts by setting the surface level of SibA (PMID:22219373), so it supports recognition rather than carrying it out. Formins (Dictyostelium ForB and ForG) build linear actin at the cup base (PMID:36897976) and could be added as a further actin annoton. The worm DYN-1 gene review places DYN-1's engulfment-cell role at phagosome maturation (GO:0090386). Mammalian dynamin 2 also acts earlier, at pseudopod extension. The dynamin family therefore appears in this module for cup closure (DNM2 evidence) and again in MODULE:phagosome_maturation (DYN-1 evidence).

12Nodes
4Parts
2Variant Sets
7Variants
23Annotons
3Connections

Derived QC

Recommended-field compliance

39.7% recommended fields populated
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Module deep research

✗ none found

No MODULE:phagocytic_engulfment deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

  • phagocytic_actin_polymerization → phagocytic_cup_closure [NOT_CHECKED]

Function consistency and core coverage

16 gene-function check(s) reflected in core functions · 0 conflict(s) · 34 evidence or coverage gap(s) (52 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
fcgr2a_igg_receptor FCGR2A
UniProtKB:P12318
Gene 		IgG receptor activity
GO:0019770 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
syk_fcgr_kinase SYK
UniProtKB:P43405
Gene 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cr3_ic3b_receptor PROTEIN_COMPLEX
Gene 		complement component iC3b receptor activity
GO:0001858 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
clec7a_beta_glucan_receptor CLEC7A
UniProtKB:Q9BXN2
Gene 		pattern recognition receptor activity
GO:0038187 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
timd4_ps_receptor TIMD4
UniProtKB:Q96H15
Gene 		phosphatidylserine binding
GO:0001786 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
gas6_ps_bridge GAS6
UniProtKB:Q14393
Gene 		phosphatidylserine binding
GO:0001786 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mertk_tam_receptor MERTK
UniProtKB:Q12866
Gene 		transmembrane receptor protein tyrosine kinase activity
GO:0004714 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
ttr52_ps_bridge ttr-52
UniProtKB:G5ED35
Gene 		protein-macromolecule adaptor activity
GO:0030674 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ced1_megf10_engulfment_receptor ced-1 (C. elegans)
UniProtKB:Q9XWD6
Family Representative 		scavenger receptor activity
GO:0005044 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ced1_megf10_engulfment_receptor drpr (Drosophila)
UniProtKB:Q9W0A0
Family Representative 		scavenger receptor activity
GO:0005044 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ced1_megf10_engulfment_receptor MEGF10 (human)
UniProtKB:Q96KG7
Family Representative 		scavenger receptor activity
GO:0005044 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ced6_gulp_adaptor ced-6 (C. elegans)
UniProtKB:O76337
Family Representative 		signaling adaptor activity
GO:0035591 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ced6_gulp_adaptor ced-6 (Drosophila)
UniProtKB:Q7JUY7
Family Representative 		signaling adaptor activity
GO:0035591 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
ced6_gulp_adaptor GULP1 (human)
UniProtKB:Q9UBP9
Family Representative 		signaling adaptor activity
GO:0035591 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
shark_draper_kinase Shark (Drosophila)
UniProtKB:Q24145
Gene 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
far1_lps_receptor far1 (Dictyostelium)
UniProtKB:Q54U89
Gene 		pattern recognition receptor activity
GO:0038187 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
siba_particle_adhesion sibA (Dictyostelium)
UniProtKB:Q54KF7
Gene 		cell adhesion mediator activity
GO:0098631 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
crk_ced2_adaptor CRK (human)
UniProtKB:P46108
Family Representative 		signaling adaptor activity
GO:0035591 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
crk_ced2_adaptor ced-2 (C. elegans)
UniProtKB:Q9NHC3
Family Representative 		signaling adaptor activity
GO:0035591 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dock180_rac_gef DOCK1 (human)
UniProtKB:Q14185
Family Representative 		guanyl-nucleotide exchange factor activity
GO:0005085 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
dock180_rac_gef ced-5 (C. elegans)
UniProtKB:G5EEN3
Family Representative 		guanyl-nucleotide exchange factor activity
GO:0005085 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
elmo_gef_adaptor ELMO1 (human)
UniProtKB:Q92556
Family Representative 		guanyl-nucleotide exchange factor adaptor activity
GO:0005091 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
elmo_gef_adaptor ced-12 (C. elegans)
UniProtKB:Q8STE5
Family Representative 		guanyl-nucleotide exchange factor adaptor activity
GO:0005091 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
elmo_gef_adaptor Ced-12 (Drosophila)
UniProtKB:Q9VKB2
Family Representative 		guanyl-nucleotide exchange factor adaptor activity
GO:0005091 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
rac_cdc42_gtpase RAC1 (human)
UniProtKB:P63000
Family Representative 		GTPase activity
GO:0003924 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
rac_cdc42_gtpase ced-10 (C. elegans)
UniProtKB:Q03206
Family Representative 		GTPase activity
GO:0003924 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
rac_cdc42_gtpase CDC42 (human)
UniProtKB:P60953
Family Representative 		GTPase activity
GO:0003924 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
rac_cdc42_gtpase rac1A (Dictyostelium)
UniProtKB:P34144
Family Representative 		GTPase activity
GO:0003924 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
rac_cdc42_gtpase racG (Dictyostelium)
UniProtKB:Q9GPS0
Family Representative 		GTPase activity
GO:0003924 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
rhoa_gtpase RHOA (human)
UniProtKB:P61586
Family Representative 		GTPase activity
GO:0003924 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
scar_wave_npf WASF2 (human)
UniProtKB:Q9Y6W5
Family Representative 		Arp2/3 complex binding
GO:0071933 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
scar_wave_npf WASF1 (human)
UniProtKB:Q92558
Family Representative 		Arp2/3 complex binding
GO:0071933 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
scar_wave_npf SCAR (Drosophila)
UniProtKB:F2FB81
Family Representative 		Arp2/3 complex binding
GO:0071933 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
scar_wave_npf scrA (Dictyostelium)
UniProtKB:Q54NF8
Family Representative 		Arp2/3 complex binding
GO:0071933 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
wasp_npf WAS (human)
UniProtKB:P42768
Family Representative 		Arp2/3 complex binding
GO:0071933 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
wasp_npf WASL (human)
UniProtKB:O00401
Family Representative 		Arp2/3 complex binding
GO:0071933 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
arp23_complex PROTEIN_COMPLEX
Gene 		actin filament binding
GO:0051015 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
class_i_pi3k PIK3CD (human)
UniProtKB:O00329
Family Representative 		1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
GO:0046934 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
class_i_pi3k PIK3CA (human)
UniProtKB:P42336
Family Representative 		1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
GO:0046934 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
class_i_pi3k PIK3CB (human)
UniProtKB:P42338
Family Representative 		1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
GO:0046934 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
dynamin_cup_closure DNM2 (human)
UniProtKB:P50570
Family Representative 		GTPase activity
GO:0003924 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ced1_megf10_engulfment_receptor CED-1/Draper/MEGF10 engulfment receptor orthogroup
PANTHER:PTHR24035
Family 		scavenger receptor activity
GO:0005044 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24035.
ced6_gulp_adaptor CED-6/GULP PTB-domain engulfment adaptor
PANTHER:PTHR11232
Family 		signaling adaptor activity
GO:0035591 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11232.
crk_ced2_adaptor CrkII/CED-2 SH2-SH3 adaptor orthogroup
PANTHER:PTHR19969
Family 		signaling adaptor activity
GO:0035591 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR19969.
dock180_rac_gef DOCK-A subfamily (DOCK180/CED-5/Myoblast city)
PANTHER:PTHR45653
Family 		guanyl-nucleotide exchange factor activity
GO:0005085 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR45653.
elmo_gef_adaptor ELMO/CED-12 family
PANTHER:PTHR12771
Family 		guanyl-nucleotide exchange factor adaptor activity
GO:0005091 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR12771.
rac_cdc42_gtpase Rac and Cdc42 Rho-family GTPases
PANTHER:PTHR24072
Family 		GTPase activity
GO:0003924 		Family Function Unreviewed
Family review leaves GO:0003924 UNRESOLVED. Full-length RHOJ is directly demonstrated to hydrolyze GTP, so RHOJ must not be labelled GTPase-deficient simply by analogy to atypical Rnd proteins. The benchmark product has a disrupted distal sequence and cannot inherit intact RHOJ kinetics. Across the broader family, nucleotide regulation and catalytic competence require branch- and product-specific evidence.
rhoa_gtpase RhoA subfamily
PANTHER:PTHR24072:SF153
Family 		GTPase activity
GO:0003924 		Family Function Unreviewed
Family review leaves GO:0003924 UNRESOLVED. Full-length RHOJ is directly demonstrated to hydrolyze GTP, so RHOJ must not be labelled GTPase-deficient simply by analogy to atypical Rnd proteins. The benchmark product has a disrupted distal sequence and cannot inherit intact RHOJ kinetics. Across the broader family, nucleotide regulation and catalytic competence require branch- and product-specific evidence.
scar_wave_npf SCAR/WAVE nucleation-promoting factors
PANTHER:PTHR12902
Family 		Arp2/3 complex binding
GO:0071933 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR12902.
wasp_npf WASP/N-WASP nucleation-promoting factors
Family 		Arp2/3 complex binding
GO:0071933 		Family Id Missing
The family has no identifier linking it to a curated family review.
class_i_pi3k class I PI3K catalytic subunits
Family 		1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
GO:0046934 		Family Id Missing
The family has no identifier linking it to a curated family review.
dynamin_cup_closure dynamin-2 subfamily
PANTHER:PTHR11566:SF23
Family 		GTPase activity
GO:0003924 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11566:SF23.

Gene-review completeness (18/45 grounded genes reviewed)

12 complete review(s) · 11 with deep research · 27 missing review · 7 reviewed but lacking deep research

Gene Review Complete Deep research
CDC42 P60953 ✓ 257/284 ✗
ced-1 Q9XWD6 ✓ ✓ ✓
ced-12 Q8STE5 ✓ ✓ ✓
Ced-12 Q9VKB2 ✓ ✓ ✓
ced-2 Q9NHC3 ✓ ✓ ✓
ced-5 G5EEN3 ✓ ✓ ✓
ced-6 O76337 ✓ ✓ ✓
DNM2 P50570 ✓ 170/171 ✗
drpr Q9W0A0 ✓ 49/51 ✓
SCAR (Drosophila) F2FB81 ✗ — —
GAS6 Q14393 ✓ ✓ ✓
ITGAM P11215 ✓ ✓ ✗
MEGF10 Q96KG7 ✓ 37/38 ✗
WASL (human) O00401 ✗ — —
arpB (Dictyostelium) O96621 ✗ — —
ITGB2 P05107 ✗ — —
FCGR2A P12318 ✗ — —
rac1A (Dictyostelium) P34144 ✗ — —
PIK3CB (human) P42338 ✗ — —
arpC (Dictyostelium) P42528 ✗ — —
WAS (human) P42768 ✗ — —
CRK (human) P46108 ✗ — —
ACTR3 (human) P61158 ✗ — —
ACTR2 (human) P61160 ✗ — —
PIK3CA P42336 ✓ ✓ ✓
PIK3CD O00329 ✓ 112/114 ✓
ced-10 (C. elegans) Q03206 ✗ — —
MERTK Q12866 ✗ — —
DOCK1 (human) Q14185 ✗ — —
Shark (Drosophila) Q24145 ✗ — —
sibA (Dictyostelium) Q54KF7 ✗ — —
scrA (Dictyostelium) Q54NF8 ✗ — —
far1 (Dictyostelium) Q54U89 ✗ — —
ced-6 (Drosophila) Q7JUY7 ✗ — —
ELMO1 (human) Q92556 ✗ — —
WASF1 (human) Q92558 ✗ — —
TIMD4 Q96H15 ✗ — —
CLEC7A Q9BXN2 ✗ — —
racG (Dictyostelium) Q9GPS0 ✗ — —
GULP1 (human) Q9UBP9 ✗ — —
WASF2 (human) Q9Y6W5 ✗ — —
RAC1 P63000 ✓ ✓ ✗
RHOA P61586 ✓ ✓ ✗
SYK P43405 ✓ 264/278 ✗
ttr-52 G5ED35 ✓ ✓ ✓

Details

Context
EukaryotaNCBITaxon:2759
phagocyteCL:0000234
phagocytic cupGO:0001891
Phagocytic engulfmentBiological Processphagocytic_engulfment
phagocytosis, engulfmentGO:0006911
Context
EukaryotaNCBITaxon:2759
phagocyteCL:0000234
phagocytic cupGO:0001891

Connections

Clustered phagocytic receptors signal (through ITAM/SYK, CRK/DOCK/ELMO, or CED-6/GULP) to activate Rho-family GTPases at the contact site.
GTP-bound Cdc42/Rac recruit and activate WASP-family NPFs and the Arp2/3 complex.
Pseudopod extension comes before PI3K- and dynamin-dependent cup closure. SYK loss, PI3K inhibition and dominant-negative dynamin 2 all arrest uptake after actin-cup formation.
Part 1: particle recognition
Particle recognition by phagocytic receptorsBiological Processparticle_recognition

A cell-surface receptor binds the particle, either directly or through an opsonin or bridging molecule. The receptors cluster and signal across the plasma membrane.

phagocytosis, recognitionGO:0006910
Variant set: Phagocytic receptor class by receptor class and target ligand (One Or More)

The receptor class decides which Rho GTPase program is used downstream (see Rho-family GTPase activation) and whether uptake is inflammatory. For example, IgG-dependent uptake triggers a respiratory burst and complement-dependent uptake does not (PMID:9831565). Receptor classes are lineage-specific, and each variant carries its own taxon context.

Fc-gamma receptor recognition of IgG-opsonized particlesSignaling Pathwayfc_gamma_receptor_recognition

Activating Fc-gamma receptors bind IgG-coated particles. ITAM phosphorylation recruits SYK, which is required for internalization after actin cups have formed.

Fc-gamma receptor signaling pathway involved in phagocytosisGO:0038096
Context
VertebrataNCBITaxon:7742
file:modules/fc_gamma_receptor_signaling.yaml
Module: Fc-gamma receptor signaling pathway
The wider Fc-gamma receptor signaling pathway is modelled in its own module.

Annotons

FCGR2A IgG receptor
fcgr2a_igg_receptor
Participant: Gene Product: FCGR2A
Gene Product:
FCGR2AUniProtKB:P12318

Function

IgG receptor activityGO:0019770

Locations

plasma membraneGO:0005886

Representative activating Fc-gamma receptor with an ITAM in its own cytoplasmic tail. It binds the Fc region of IgG on opsonized particles and starts phagocytic signaling when clustered.

SYK kinase downstream of Fc-gamma receptors
syk_fcgr_kinase
Participant: Gene Product: SYK
Gene Product:
SYKUniProtKB:P43405

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

Locations

cytosolGO:0005829

Binds phosphorylated receptor ITAMs and phosphorylates downstream substrates. It is needed to go from actin-cup formation to internalization of IgG-opsonized particles, but not for uptake of latex beads or E. coli.

PMID:9314552
A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages.
Syk-deficient macrophages make actin cups but do not internalize Fc-gamma receptor-bound particles.
Syk is required for FcγR-induced phagocytosis, but not for phagocytosis of latex beads or microorganisms.
Complement receptor 3 recognition of iC3b-opsonized particlesBiological Processcomplement_receptor_3_recognition

The integrin alphaM-beta2 heterodimer (CR3, Mac-1) binds iC3b on complement-opsonized particles. Uptake is RhoA-dependent ("type II") and is not accompanied by a respiratory burst.

Context
VertebrataNCBITaxon:7742

Annotons

CR3 (integrin alphaM-beta2) iC3b receptor
cr3_ic3b_receptor
Participant: Protein Complex: complement receptor 3 (integrin alphaM-beta2)
Protein Complex:
complement receptor 3 (integrin alphaM-beta2)GO:0034688
Active units:
ITGAM (CD11b) alpha subunit
Participant: Gene Product: ITGAM
Gene Product:
ITGAMUniProtKB:P11215
Role: ligand-binding alpha chain
ITGB2 (CD18) beta subunit
Participant: Gene Product: ITGB2
Gene Product:
ITGB2UniProtKB:P05107
Role: signaling beta chain

Function

complement component iC3b receptor activityGO:0001858

Locations

plasma membraneGO:0005886

Binds iC3b on complement-opsonized particles and drives RhoA-dependent phagocytosis.

PMID:9831565
Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases.
Complement receptor phagocytosis is a distinct, Rho-mediated mechanism.
type II, used by the complement receptor, is mediated by Rho
Dectin-1 recognition of beta-glucan particlesBiological Processbeta_glucan_recognition

Non-opsonic recognition of fungal cell-wall beta-glucans by the C-type lectin receptor Dectin-1 (CLEC7A).

Context
VertebrataNCBITaxon:7742

Annotons

Dectin-1 beta-glucan receptor
clec7a_beta_glucan_receptor
Participant: Gene Product: CLEC7A
Gene Product:
CLEC7AUniProtKB:Q9BXN2

Function

pattern recognition receptor activityGO:0038187
Targets: (1->3)-beta-D-glucan

Locations

plasma membraneGO:0005886

Main macrophage receptor for non-opsonic beta-glucan particles such as zymosan.

PMID:12163569
Dectin-1 is a major beta-glucan receptor on macrophages.
Dectin-1 mediates beta-glucan-dependent, non-opsonic zymosan recognition by primary macrophages.
Dectin-1 was almost exclusively responsible for the beta-glucan-dependent, nonopsonic recognition of zymosan
Apoptotic-cell recognition (efferocytic receptors)Biological Processapoptotic_cell_recognition

Recognition of apoptotic cells, mainly through exposed phosphatidylserine. Recognition can be direct (TIMD4) or through a bridging ligand (GAS6 to MERTK, TTR-52 to CED-1). The CED-1/Draper/MEGF10 receptor family and its PTB-domain adaptor CED-6/GULP form a conserved receptor-adaptor unit. In Drosophila, Draper also signals through its ITAM to the Syk-family kinase Shark.

engulfment of apoptotic cellGO:0043652
Context
BilateriaNCBITaxon:33213

Annotons

TIMD4 phosphatidylserine receptor
timd4_ps_receptor
Participant: Gene Product: TIMD4
Gene Product:
TIMD4UniProtKB:Q96H15

Function

phosphatidylserine bindingGO:0001786

Locations

plasma membraneGO:0005886

Binds phosphatidylserine on apoptotic cells and tethers them to the phagocyte. It is a tethering receptor that works with signaling co-receptors.

PMID:17960135
Identification of Tim4 as a phosphatidylserine receptor.
An antibody that blocks phosphatidylserine-dependent engulfment of apoptotic cells recognizes Tim4.
strongly inhibited the phosphatidylserine-dependent engulfment of apoptotic cells

Vertebrate-specific receptor, modelled as a human gene product.

GAS6 phosphatidylserine bridging ligand
gas6_ps_bridge
Participant: Gene Product: GAS6
Gene Product:
GAS6UniProtKB:Q14393

Function

phosphatidylserine bindingGO:0001786

Locations

extracellular regionGO:0005576

Secreted Gla-domain protein. It binds phosphatidylserine on apoptotic membranes and links them to TAM receptor tyrosine kinases such as MERTK.

file:genes/human/GAS6/GAS6-ai-review.yaml
GAS6 gene review
The GAS6 review core functions include phosphatidylserine binding (GO:0001786) for efferocytosis and TAM receptor ligand activity.

Vertebrate-specific bridging ligand, modelled as a human gene product.

MERTK TAM receptor tyrosine kinase
mertk_tam_receptor
Participant: Gene Product: MERTK
Gene Product:
MERTKUniProtKB:Q12866

Function

transmembrane receptor protein tyrosine kinase activityGO:0004714

Locations

plasma membraneGO:0005886

Signaling receptor for GAS6/PROS1-bridged apoptotic cells. Ligand-induced kinase activity promotes cytoskeletal engulfment signaling.

Vertebrate-specific receptor, modelled as a human gene product. The primary MERTK efferocytosis paper (PMID:11346799, Scott et al. 2001) could not be cached (no abstract), so this annoton rests on the GAS6 review and on the TAM bridging model.

TTR-52 phosphatidylserine bridging molecule (C. elegans)
ttr52_ps_bridge
Participant: Gene Product: ttr-52
Gene Product:
ttr-52UniProtKB:G5ED35

Function

protein-macromolecule adaptor activityGO:0030674

Locations

cell surfaceGO:0009986

Secreted transthyretin-like protein of the C. elegans CED-1 route. It binds phosphatidylserine on apoptotic cells and the EMI domain of CED-1, bridging the corpse to the engulfing cell. It plays the bridging role that GAS6 and C1q play upstream of mammalian receptors; it is modelled as a single gene product because no cross-species family for it has been established here.

PMID:20526330
Caenorhabditis elegans transthyretin-like protein TTR-52 mediates recognition of apoptotic cells by the CED-1 phagocyte receptor.
TTR-52 binds both phosphatidylserine and the CED-1 extracellular domain.
TTR-52 recognizes surface-exposed phosphatidylserine (PtdSer) in vivo and binds to both PtdSer and the extracellular domain of CED-1 in vitro
file:genes/worm/ttr-52/ttr-52-ai-review.yaml
ttr-52 gene review
The ttr-52 review gives protein-macromolecule adaptor activity (GO:0030674) in recognition of apoptotic cell as the core function.
CED-1/MEGF10 engulfment receptor
ced1_megf10_engulfment_receptor
Participant: Family: CED-1/Draper/MEGF10 engulfment receptor orthogroup
Family:
CED-1/Draper/MEGF10 engulfment receptor orthogroupPANTHER:PTHR24035 Multiple-EGF-like-domain transmembrane receptors with NPxY/YxxL cytoplasmic motifs. Grounded on PANTHER's own classification (ced-1 and Draper in SF109, MEGF10 in SF136), not on the UniProt/InterPro cross-references, which name PTHR24043 and PTHR24052 (see projects/PANTHER_FAMILY_ASSIGNMENT_DISCREPANCIES.md).
Representative Members: ced-1 (C. elegans)UniProtKB:Q9XWD6 drpr (Drosophila)UniProtKB:Q9W0A0 MEGF10 (human)UniProtKB:Q96KG7

Function

scavenger receptor activityGO:0005044

Processes

engulfment of apoptotic cellGO:0043652

Locations

plasma membraneGO:0005886

Clusters around cell corpses and signals through cytoplasmic tail motifs that bind PTB and SH2 domains. These motifs are needed for engulfment but not for clustering.

PMID:11163239
CED-1 is a transmembrane receptor that mediates cell corpse engulfment in C. elegans.
CED-1 is a cell-surface phagocytic receptor that recognizes cell corpses.
CED-1 is a cell surface phagocytic receptor that recognizes cell corpses
PMID:27170117
Megf10 Is a Receptor for C1Q That Mediates Clearance of Apoptotic Cells by Astrocytes.
Megf10 binds the eat-me signal C1q, and its expression confers apoptotic-cell phagocytosis.
Megf10 binds with high affinity to C1q, an eat-me signal for apoptotic cells
file:genes/worm/ced-1/ced-1-ai-review.yaml
ced-1 gene review
The ced-1 review gives scavenger receptor activity (GO:0005044) in engulfment and recognition of apoptotic cells as the core function.
file:genes/human/MEGF10/MEGF10-ai-review.yaml
MEGF10 gene review
The MEGF10 review gives scavenger receptor activity (GO:0005044) in engulfment of apoptotic cell, and C1q complex binding, as core functions.
CED-6/GULP engulfment adaptor
ced6_gulp_adaptor
Participant: Family: CED-6/GULP PTB-domain engulfment adaptor
Family:
CED-6/GULP PTB-domain engulfment adaptorPANTHER:PTHR11232
Representative Members: ced-6 (C. elegans)UniProtKB:O76337 ced-6 (Drosophila)UniProtKB:Q7JUY7 GULP1 (human)UniProtKB:Q9UBP9

Function

signaling adaptor activityGO:0035591

Processes

phagocytosis, engulfmentGO:0006911

Locations

cytosolGO:0005829

PTB-domain adaptor that binds the NPxY motif of CED-1/MEGF10 (and LRP1) tails and passes the signal on toward actin remodeling and dynamin recruitment.

PMID:9635426
Candidate adaptor protein CED-6 promotes the engulfment of apoptotic cells in C. elegans.
CED-6 is an adaptor in the engulfing cell that mediates recognition and engulfment of apoptotic cells.
CED-6 is an adaptor molecule acting in a signal transduction pathway that specifically mediates the recognition and engulfment of apoptotic cells
file:genes/worm/ced-6/ced-6-ai-review.yaml
ced-6 gene review
The ced-6 review gives signaling adaptor activity (GO:0035591) in engulfment of apoptotic cell as the core function, binding the CED-1 NPXY motif through its PTB domain.
Shark Syk-family kinase downstream of Draper
shark_draper_kinase
Participant: Gene Product: Shark (Drosophila)
Gene Product:
Shark (Drosophila)UniProtKB:Q24145

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

Locations

cytosolGO:0005829

Binds the ITAM in the Draper cytoplasmic tail, which the Src-family kinase Src42A phosphorylates, and is required for glia to engulf neuronal corpses and axon debris. This is the same ITAM-Src-Syk logic used by vertebrate Fc-gamma receptors.

PMID:18432193
Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signalling.
Shark binds the Draper ITAM and is required for Draper-dependent glial engulfment.
binds Draper through an immunoreceptor tyrosine-based activation motif (ITAM) in the Draper intracellular domain
PMID:18432193
Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signalling.
Loss of Shark activity blocks Draper signalling in vivo.
Shark activity is essential for Draper-mediated signalling events in vivo
Bacterial recognition by amoebal receptorsBiological Processamoebal_bacterial_recognition

Dictyostelium amoebae have no Fc-gamma or complement receptors. They recognize bacteria through the folate/LPS receptor fAR1, a G-protein-coupled receptor, and adhere to particles through the transmembrane protein SibA. Loss of either reduces uptake of particles or bacteria.

Context
Dictyostelium discoideumNCBITaxon:44689

Annotons

fAR1 folate and LPS receptor
far1_lps_receptor
Participant: Gene Product: far1 (Dictyostelium)
Gene Product:
far1 (Dictyostelium)UniProtKB:Q54U89

Function

pattern recognition receptor activityGO:0038187
Targets: lipopolysaccharide

Locations

plasma membraneGO:0005886

G-protein-coupled receptor whose extracellular Venus-flytrap domain binds folate and bacterial LPS. Through its heterotrimeric G protein it reorganizes actin for both chemotaxis toward bacteria and their engulfment.

PMID:29799847
A G-protein-coupled chemoattractant receptor recognizes lipopolysaccharide for bacterial phagocytosis.
far1-null cells, and cells lacking its G proteins, are defective in phagocytosis of Klebsiella.
Cells lacking fAR1 or its cognate G-proteins are defective in chemotaxis toward folate and phagocytosis of Klebsiella aerogenes
PMID:29799847
A G-protein-coupled chemoattractant receptor recognizes lipopolysaccharide for bacterial phagocytosis.
The fAR1 Venus-flytrap domain binds LPS.
the extracellular Venus-Flytrap (VFT) domain of fAR1 acts as the binding site for both folate and LPS
SibA particle adhesion protein
siba_particle_adhesion
Participant: Gene Product: sibA (Dictyostelium)
Gene Product:
sibA (Dictyostelium)UniProtKB:Q54KF7

Function

cell adhesion mediator activityGO:0098631

Locations

plasma membraneGO:0005886

Type I transmembrane protein with integrin-beta-like features whose cytoplasmic tail binds talin. It is needed for amoebae to adhere to phagocytic particles. Its surface level depends on the TM9 protein Phg1A.

PMID:16699495
An adhesion molecule in free-living Dictyostelium amoebae with integrin beta features.
sibA inactivation reduces adhesion to phagocytic particles.
genetic inactivation of SIBA affects adhesion to phagocytic particles
PMID:22219373
TM9/Phg1 and SadA proteins control surface expression and stability of SibA adhesion molecules in Dictyostelium.
Phg1A controls how much SibA reaches the cell surface.
genetic inactivation of the TM9 protein Phg1A dramatically decreases the surface levels of the SibA adhesion molecule
Part 2: Rho-family GTPase activation
Rho-family GTPase activation at the phagocytic cupSignaling Pathwayrho_gtpase_activation

Receptor signaling activates Rho-family GTPases at the site of particle contact. The receptor class decides which GTPases are used.

Variant set: Phagocytic Rho-GTPase program by Rho GTPase used (set by receptor class) (One Or More)

Type I (Fc-gamma receptor; also apoptotic-cell receptors through DOCK1/ELMO1) uses Rac and Cdc42. Type II (CR3) uses RhoA (PMID:9831565). In C. elegans both corpse-engulfment routes converge on CED-10/Rac (PMID:15744306). In Dictyostelium, Rac1 and RacG act in phagocytosis (PMID:10825297, PMID:16950926), but the CRK/DOCK/ELMO route has not been shown to activate them during amoebal uptake.

Rac/Cdc42 program (type I)Signaling Pathwayrac_cdc42_program

The CRK adaptor recruits the DOCK180-ELMO bipartite GEF, which loads GTP onto Rac. Cdc42 and Rac then recruit WASP-family nucleation-promoting factors. The same unit (CED-2, CED-5, CED-12, CED-10) works in C. elegans corpse engulfment.

Annotons

CRK/CED-2 SH2-SH3 adaptor
crk_ced2_adaptor
Participant: Family: CrkII/CED-2 SH2-SH3 adaptor orthogroup
Family:
CrkII/CED-2 SH2-SH3 adaptor orthogroupPANTHER:PTHR19969
Representative Members: CRK (human)UniProtKB:P46108 ced-2 (C. elegans)UniProtKB:Q9NHC3

Function

signaling adaptor activityGO:0035591

Locations

cytosolGO:0005829

SH2-SH3 adaptor that binds phosphotyrosine signals through its SH2 domain and brings DOCK180/CED-5 in through its SH3 domain.

PMID:10707082
CED-2/CrkII and CED-10/Rac control phagocytosis and cell migration in Caenorhabditis elegans.
CED-2 binds CED-5 and acts upstream of CED-10 in engulfing cells.
CED-2 and CED-5 physically interact
file:genes/worm/ced-2/ced-2-ai-review.yaml
ced-2 gene review
The ced-2 review gives signaling adaptor activity (GO:0035591) in engulfment of apoptotic cell, Rac protein signal transduction and distal tip cell migration as core functions.

Phagocytic role shown in nematodes and mammals. No CRK ortholog with a phagocytic role is known in amoebae.

DOCK180/CED-5 Rac guanine-nucleotide exchange factor
dock180_rac_gef
Participant: Family: DOCK-A subfamily (DOCK180/CED-5/Myoblast city)
Family:
DOCK-A subfamily (DOCK180/CED-5/Myoblast city)PANTHER:PTHR45653
Representative Members: DOCK1 (human)UniProtKB:Q14185 ced-5 (C. elegans)UniProtKB:G5EEN3

Function

guanyl-nucleotide exchange factor activityGO:0005085
Targets: Rac1 / CED-10

Locations

cytosolGO:0005829

Catalytic half of the bipartite DOCK180-ELMO GEF. Its DHR-2 (Docker) domain binds nucleotide-free Rac and loads it with GTP.

PMID:12134158
Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex.
The Dock180 Docker domain mediates GTP loading of Rac, and a Dock180-ELMO1 interaction is required in cells.
a Dock180 ELMO1 interaction is required
PMID:9548255
C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180.
CED-5 is the C. elegans DOCK180 ortholog required for cell-corpse engulfment.
encodes a protein that is similar to the human protein DOCK180
file:genes/worm/ced-5/ced-5-ai-review.yaml
ced-5 gene review
The ced-5 review gives guanyl-nucleotide exchange factor activity (GO:0005085) in engulfment of apoptotic cell and distal tip cell migration as core functions.

GEF activity is placed at a eukaryote-level PAINT node, and Dictyostelium DockD acts on Rac with an ELMO partner during motility (PMID:19037099). A phagocytic role for DOCK-A proteins is shown only in nematodes, insects and mammals. PANTHER puts ced-5 in SF10 (MYOBLAST CITY) and DOCK1 in SF1, so the family-level id is used.

ELMO/CED-12 GEF adaptor
elmo_gef_adaptor
Participant: Family: ELMO/CED-12 family
Family:
ELMO/CED-12 familyPANTHER:PTHR12771
Representative Members: ELMO1 (human)UniProtKB:Q92556 ced-12 (C. elegans)UniProtKB:Q8STE5 Ced-12 (Drosophila)UniProtKB:Q9VKB2

Function

guanyl-nucleotide exchange factor adaptor activityGO:0005091

Locations

cytosolGO:0005829

Binds DOCK180/CED-5 and is required for its Rac GEF activity in cells. ELMO is the non-catalytic partner of the bipartite GEF.

PMID:11595183
CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration.
CED-12/ELMO binds CED-5/Dock180 and the complex stimulates Rac activation.
this evolutionarily conserved complex stimulates a Rac-GEF
file:genes/DROME/Ced-12/Ced-12-ai-review.yaml
Drosophila Ced-12 gene review
The Ced-12 review gives guanyl-nucleotide exchange factor adaptor activity (GO:0005091) as the core MF.
file:genes/worm/ced-12/ced-12-ai-review.yaml
ced-12 gene review
The ced-12 review gives guanyl nucleotide exchange factor activator activity (GO:0160124) in engulfment of apoptotic cell and distal tip cell migration as core functions. This differs from the GEF adaptor term used here and in the Drosophila Ced-12 review; the two reviews have not yet been reconciled.

Phagocytic role shown in nematodes, insects and mammals. Dictyostelium ElmoA falls in the same PANTHER subfamily as worm and fly CED-12 (PTHR12771:SF56), but elmoA-null cells engulf faster (PMID:18854143), so ElmoA is not used as an exemplar. PANTHER's own files place worm CED-12 (Q8STE5) in SF56 although its UniProt entry has no PANTHER cross-reference.

Rac/CED-10 and Cdc42 GTPases
rac_cdc42_gtpase
Participant: Family: Rac and Cdc42 Rho-family GTPases
Family:
Rac and Cdc42 Rho-family GTPasesPANTHER:PTHR24072
Representative Members: RAC1 (human)UniProtKB:P63000 ced-10 (C. elegans)UniProtKB:Q03206 CDC42 (human)UniProtKB:P60953 rac1A (Dictyostelium)UniProtKB:P34144 racG (Dictyostelium)UniProtKB:Q9GPS0

Function

GTPase activityGO:0003924

Locations

plasma membraneGO:0005886

Molecular switches activated at the phagocytic cup. In the GTP form they recruit WASP-family and PAK effectors that drive actin polymerization.

PMID:9831565
Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases.
Fc-gamma receptor (type I) phagocytosis requires Cdc42 and Rac.
Type I, used by the immunoglobulin receptor, is mediated by Cdc42 and Rac
PMID:15744306
Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans.
Both C. elegans engulfment routes converge on CED-10/Rac.
CED-2, CED-5 and CED-12 (mammalian homologues CrkII, Dock180 and ELMO, respectively) function to activate CED-10 (Rac1)
PMID:10825297
Rac1 GTPases control filopodia formation, cell motility, endocytosis, cytokinesis and development in Dictyostelium.
In Dictyostelium, constitutively active Rac1 mutants act as dominant negatives and severely impair phagocytosis.
these mutants were severely impaired in cell motility, colony growth, phagocytosis, pinocytosis, cytokinesis and development
PMID:16950926
RacG regulates morphology, phagocytosis, and chemotaxis.
Dictyostelium RacG concentrates at the rim of the forming phagocytic cup, and its overexpression increases uptake.
RacG is enriched at the rim of the progressing phagocytic cup
RhoA program (type II, CR3)Signaling Pathwayrhoa_program

Complement receptor 3 uptake depends on RhoA, which drives a different actin assembly: particles sink into the cell with few pseudopods.

Shown for the vertebrate CR3 route only. No RhoA-dependent uptake route has been described in amoebae.

Annotons

RhoA GTPase
rhoa_gtpase
Participant: Family: RhoA subfamily
Family:
RhoA subfamilyPANTHER:PTHR24072:SF153
Representative Members: RHOA (human)UniProtKB:P61586

Function

GTPase activityGO:0003924

Locations

plasma membraneGO:0005886

Rho-family switch needed for complement-receptor (type II) phagocytosis.

PMID:9831565
Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases.
Complement receptor phagocytosis is mediated by Rho.
type II, used by the complement receptor, is mediated by Rho
Part 3: actin polymerization for pseudopod extension
Arp2/3-dependent actin polymerizationBiological Processphagocytic_actin_polymerization

Active Rho GTPases recruit WASP-family nucleation-promoting factors (SCAR/WAVE downstream of Rac, WASP/N-WASP downstream of Cdc42) that activate the Arp2/3 complex. Branched actin then pushes pseudopods around the particle. Arp2/3 is used by both Fc-gamma receptor and CR3 uptake (PMID:10783245) and is recruited to the phagocytic cup of Dictyostelium (PMID:11807934).

Arp2/3 complex-mediated actin nucleationGO:0034314

Annotons

SCAR/WAVE nucleation-promoting factor
scar_wave_npf
Participant: Family: SCAR/WAVE nucleation-promoting factors
Family:
SCAR/WAVE nucleation-promoting factorsPANTHER:PTHR12902
Representative Members: WASF2 (human)UniProtKB:Q9Y6W5 WASF1 (human)UniProtKB:Q92558 SCAR (Drosophila)UniProtKB:F2FB81 scrA (Dictyostelium)UniProtKB:Q54NF8

Function

Arp2/3 complex bindingGO:0071933

Locations

phagocytic cupGO:0001891

Rac-activated nucleation-promoting factor, part of the WAVE regulatory complex. It collects at the protruding rim of the phagocytic cup and activates the Arp2/3 complex there.

PMID:11683394
The WASp-like protein scar regulates macropinocytosis, phagocytosis and endosomal membrane flow in Dictyostelium.
scar-null Dictyostelium cells have reduced rates of phagocytosis.
Rates of fluid phase macropinocytosis and phagocytosis are significantly reduced in the scar- cell-line
PMID:12919849
Identification of cytoskeletal regulatory proteins required for efficient phagocytosis in Drosophila.
D-SCAR loss reduces phagocytosis of bacteria by Drosophila hemocytes and S2 cells.
lack of D-SCAR significantly decreased phagocytosis of Escherichia coli and Staphylococcus aureus
PMID:36897976
Convergence of Ras- and Rac-regulated formin pathways is pivotal for phagosome formation and particle uptake in Dictyostelium.
SCAR collects as a ring along the cup edge, and its loss reduces F-actin at the cup rim.
inactivation of SCAR in Dictyostelium, which accumulates in a ring-like fashion along the cup edge (17), diminishes F-actin at the protrusive cup rim
WASP/N-WASP nucleation-promoting factor
wasp_npf
Participant: Family: WASP/N-WASP nucleation-promoting factors
Family:
WASP/N-WASP nucleation-promoting factors
Representative Members: WAS (human)UniProtKB:P42768 WASL (human)UniProtKB:O00401

Function

Arp2/3 complex bindingGO:0071933

Locations

phagocytic cupGO:0001891

Cdc42-GTP binding releases autoinhibition. The C-terminal VCA region then binds and activates the Arp2/3 complex at the phagocytic cup.

PMID:12919849
Identification of cytoskeletal regulatory proteins required for efficient phagocytosis in Drosophila.
RNAi in Drosophila S2 cells shows that D-WASp also takes part in phagocytosis.
RNA interference studies in S2 cells indicated that the D-SCAR homolog D-WASp also participates in phagocytosis

WASP is restricted to hematopoietic cells, and N-WASP is ubiquitous. Neither has a cached phagocytosis-specific primary paper here, so the mammalian side rests on the review literature (PMID:25319336) and on the Arp2/3 requirement (PMID:10783245). The SCAR/WAVE annoton above is the NPF with loss-of-function evidence in both amoebae and insects.

Arp2/3 complex
arp23_complex
Participant: Protein Complex: Arp2/3 complex
Protein Complex:
Arp2/3 complexGO:0005885
Active units:
ARP2
Participant: Family: ARP2 (actin-related protein 2)
Family:
ARP2 (actin-related protein 2)
Representative Members: ACTR2 (human)UniProtKB:P61160 arpB (Dictyostelium)UniProtKB:O96621
Role: actin-related nucleating subunit
ARP3
Participant: Family: ARP3 (actin-related protein 3)
Family:
ARP3 (actin-related protein 3)
Representative Members: ACTR3 (human)UniProtKB:P61158 arpC (Dictyostelium)UniProtKB:P42528
Role: actin-related nucleating subunit

Function

actin filament bindingGO:0051015

Processes

Arp2/3 complex-mediated actin nucleationGO:0034314

Locations

phagocytic cupGO:0001891

Binds the side of an existing filament and nucleates a branch, building the dendritic actin network that pushes pseudopods out.

PMID:10783245
Involvement of the Arp2/3 complex in phagocytosis mediated by FcgammaR or CR3.
The Arp2/3 complex is involved in both Fc-gamma receptor and CR3 phagocytosis (title-level citation; no abstract cached).
PMID:11807934
Dynamics of the Dictyostelium Arp2/3 complex in endocytosis, cytokinesis, and chemotaxis.
In Dictyostelium the Arp2/3 complex is recruited within seconds to sites of phagocytosis.
in phagocytosis, macropinocytosis, and chemotaxis the complex is recruited within seconds to sites where actin polymerization is induced
PMID:16950926
RacG regulates morphology, phagocytosis, and chemotaxis.
In a Dictyostelium cell-free system, a phagocytic-cup Rac GTPase drives actin polymerization through Arp2/3.
In a cell-free system, RacG stimulates actin polymerization through the Arp2/3 complex.
Part 4: phagocytic cup closure and internalization
Pseudopod extension completion and phagocytic cup closureBiological Processphagocytic_cup_closure

Class I PI3K turns over PI(4,5)P2 at the cup base, which ends actin polymerization. Dynamin is recruited to the forming phagosome. Both are needed for pseudopods to finish extending and for the cup to seal into a nascent phagosome. Blocking either arrests uptake at the same stage, after actin-cup formation.

Annotons

Class I PI3K catalytic subunit
class_i_pi3k
Participant: Family: class I PI3K catalytic subunits
Family:
class I PI3K catalytic subunits
Representative Members: PIK3CD (human)UniProtKB:O00329 PIK3CA (human)UniProtKB:P42336 PIK3CB (human)UniProtKB:P42338

Function

1-phosphatidylinositol-4,5-bisphosphate 3-kinase activityGO:0046934

Locations

phagocytic cupGO:0001891

Makes PI(3,4,5)P3 in the nascent phagocytic cup. This is needed for optimal phagocytosis but not for later phagosome maturation.

PMID:11581283
Distinct roles of class I and class III phosphatidylinositol 3-kinases in phagosome formation and maturation.
Class I PI3K products appear in the nascent cup, and class I PI3K is required for optimal phagocytosis but not maturation.
optimal phagocytosis, but not maturation, requires this type of enzyme
PMID:9314552
A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages.
PI3K inhibitors block Fc-gamma receptor phagocytosis after actin-cup formation.
inhibitors of phosphatidylinositol 3-kinase also blocked FcgammaR-mediated phagocytosis at this stage
file:genes/human/PIK3CD/PIK3CD-ai-review.yaml
PIK3CD gene review
The PIK3CD review gives 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity (GO:0046934) as the core MF.
PMID:15572406
In vivo analysis of 3-phosphoinositide dynamics during Dictyostelium phagocytosis and chemotaxis.
In Dictyostelium the class I PI3K product PI(3,4,5)P3 rises transiently at engulfment sites. This shows the same lipid step in amoebae but is not loss-of-function evidence.
During phagocytosis and macropinocytosis PtdIns(3,4,5)P3 levels transiently increased at sites of engulfment

The requirement for class I PI3K at cup closure is shown in mammalian macrophages. Amoebal representatives are not listed because a phagocytosis defect in Dictyostelium pikA/pikB mutants was not found in the literature reviewed here.

Dynamin GTPase at the forming phagosome
dynamin_cup_closure
Participant: Family: dynamin-2 subfamily
Family:
dynamin-2 subfamilyPANTHER:PTHR11566:SF23
Representative Members: DNM2 (human)UniProtKB:P50570

Function

GTPase activityGO:0003924

Locations

phagocytic cupGO:0001891

Collects on early phagosomes in a PI3K-dependent way. It is needed for membrane extension around the particle and is thought to help deliver focal membrane and seal the phagosome.

PMID:10601359
Dynamin 2 is required for phagocytosis in macrophages.
Dominant-negative dynamin 2 blocks internalization at the membrane-extension stage, and PI3K inhibition prevents dynamin recruitment.
significantly inhibits particle internalization at the stage of membrane extension around the particle
PMID:9880338
Disruption of a dynamin homologue affects endocytosis, organelle morphology, and cytokinesis in Dictyostelium discoideum.
Dictyostelium dynamin A acts on endo-lysosomal membranes and not at the plasma membrane, which limits this step to the animal evidence.
dynamin A is likely to function in membrane trafficking processes along the endo-lysosomal pathway of D. discoideum but not at the plasma membrane

Grounded on the vertebrate dynamin-2 subfamily because the evidence for a role at cup closure is from mammalian macrophages. Nematode DYN-1 acts mainly in phagosome maturation, and Dictyostelium dynamin A works on endo-lysosomal membranes rather than the plasma membrane. Whether any dynamin closes the phagocytic cup in amoebae is open.