Proximal B cell receptor signaling

Antigen-engaged B-cell receptors use CD79 signaling tails, SYK and BLNK to organize tyrosine phosphorylation. Class IA PI3K supplies PIP3 for BTK recruitment, and BTK promotes PLCG2-dependent IP3 and DAG production. CD19, BCAP and LYN modulate this network according to receptor and cellular context.

MODULE:b_cell_receptor_signalingDRAFTCONCRETESignaling Pathwaymodules/b_cell_receptor_signaling.yaml
B cell receptor signaling pathwayGO:0050853
PMID:19827951
B cell signaling and fate decision.
Antigen-triggered and antigen-independent developmental signaling require distinct contexts. The module will cover proximal antigen-triggered signaling; tonic survival and downstream cell-fate programs are interfaces.
also control a series of antigen-independent checkpoints during B cell development.
PMID:24167721
B lymphocyte antigen receptor signaling: initiation, amplification, and regulation.
BLNK is a phosphotyrosine scaffold connecting kinase activity to effector recruitment. LYN also has inhibitory roles and CD19/BCAP contributions vary with stimulus; a rigid linear kinase chain is insufficient.
Phospho-Blnk serves as a scaffold for the assembly of the other components
PMID:23551098
Rules of engagement: distinct functions for the four class I PI3K catalytic isoforms in immunity.
Class IA p85-associated PI3K and class IB p110-gamma are distinct recruitment architectures. Antigen-dependent delta signaling must be separated from alpha/delta compensation in tonic signaling.
p110γ which is bound by a Gβγ-binding p101 or p84 regulatory subunit is preferentially activated by G-protein coupled receptors.
PMID:39256626
Towards a unifying model for B-cell receptor triggering.
No single triggering mechanism is established across BCR isotypes and antigen formats. Engaged membrane immunoglobulin is an upstream input, rather than a claimed universal conformational activation step.
there is still no unifying molecular mechanism
PMID:38203179
B-Cell Receptor Signaling and Beyond: The Role of Igα (CD79a)/Igβ (CD79b) in Normal and Malignant B Cells.
CD79 chains combine receptor assembly, ITAM signaling and non-ITAM recruitment roles. Mouse CD79a Y204 is highlighted for BLNK recruitment; do not transpose residue numbering to human.
mCD79a Y204 phosphorylation is of particular importance for BLNK recruitment.
PMID:39917832
Signaling Activation and Modulation in Extrafollicular B Cell Responses.
PI3K lipid production recruits PH-domain effectors before the BTK/PLCG2 output step. Downstream extrafollicular fate decisions integrate other receptors and are outside the proximal module.
production results in the recruitment of BTK and AKT to the plasma membrane
PMID:23454429
B cell receptor accessory molecule CD79α: characterisation and expression analysis in a cartilaginous fish, the spiny dogfish (Squalus acanthias).
Shark CD79-alpha sequence/expression extends evolutionary context but does not establish the full mammalian network or even the same physical receptor assembly.
If an association of shark Ig and CD79α can be proved

The required implementation specifies reviewed human components of an antigen-triggered proximal circuit. Tonic/pre-B survival, immunoglobulin repertoire generation, downstream calcium channels, PKC, NF-kappaB, MAPK and transcription are interfaces. Human, mouse and chicken enumerate the evidence sample, not a claim that these species exhaust BCR biology. Shark CD79 sequence/expression does not prove conservation of this entire circuit. Exact gene selectors prevent broad kinase-family or PI3K-isoform substitution. Original PAINT nodes are not repeated as blanket pathway ancestors; their family-specific annotation provenance remains in individual reviews. All 22 member reviews are complete. Comparative activity evidence distinguishes native assays, heterologous constructs, biochemical chemistry and explicit ortholog inference. The CD79B contribution descriptors intentionally omit a standalone molecular-function id because the gene cores support contribution to receptor activity, whereas CD79A additionally has specific SYK/BLNK recruitment evidence for adaptor activity. This does not deny ITAM signaling by CD79B or equate missing ids with missing function; it avoids assigning the isolated-chain receptor function to a descriptor that cannot encode contributes_to. Full repository validation passed before this focused follow-up; external review is being addressed.

22Nodes
21Parts
0Variant Sets
0Variants
20Annotons
12Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✓ present

  • b_cell_receptor_signaling-deep-research-falcon.md (falcon)

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

21 gene-function check(s) reflected in core functions · 0 conflict(s) · 20 evidence or coverage gap(s) (49 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
human_cd79_signaling_assembly PROTEIN_COMPLEX
Gene 		ITAM-dependent signal transduction by the CD79 assembly
No function ID 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
human_cd79_signaling_assembly/human_cd79a_unit CD79A
UniProtKB:P11912
Complex Unit 		signaling receptor complex adaptor activity
GO:0030159 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
human_cd79_signaling_assembly/human_cd79b_unit CD79B
UniProtKB:P40259
Complex Unit 		contribution to signaling by the BCR complex
No function ID 		No Function Id
A gene review exists, but this function lacks a GO identifier. Free-text chemistry is not automatically compared.
human_syk_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).
human_blnk_adaptor BLNK
UniProtKB:Q8WV28
Gene 		signaling adaptor activity
GO:0035591 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
human_class_ia_pi3k PROTEIN_COMPLEX
Gene 		1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
GO:0046934 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
human_class_ia_pi3k/human_p110delta_unit PIK3CD
UniProtKB:O00329
Complex Unit 		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).
human_class_ia_pi3k/human_p85alpha_unit PIK3R1
UniProtKB:P27986
Complex Unit 		1-phosphatidylinositol-3-kinase regulator activity
GO:0046935 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
human_btk_pip3_binding BTK
UniProtKB:Q06187
Gene 		phosphatidylinositol-3,4,5-trisphosphate binding
GO:0005547 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
human_btk_kinase BTK
UniProtKB:Q06187
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).
human_plcg2_plc PLCG2
UniProtKB:P16885
Gene 		phosphatidylinositol-4,5-bisphosphate phospholipase C activity
GO:0004435 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
human_cd19_receptor_adaptor CD19
UniProtKB:P15391
Gene 		signaling receptor complex adaptor activity
GO:0030159 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
human_pik3ap1_p85_binding PIK3AP1
UniProtKB:Q6ZUJ8
Gene 		phosphatidylinositol 3-kinase regulatory subunit binding
GO:0036312 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
human_lyn_kinase LYN
UniProtKB:P07948
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).
mouse_cd79_signaling_assembly PROTEIN_COMPLEX
Gene 		ITAM-dependent signal transduction by the CD79 assembly
No function ID 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
mouse_cd79_signaling_assembly/mouse_cd79a_unit Cd79a
UniProtKB:P11911
Complex Unit 		signaling receptor complex adaptor activity
GO:0030159 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mouse_cd79_signaling_assembly/mouse_cd79b_unit Cd79b
UniProtKB:P15530
Complex Unit 		contribution to signaling by the BCR complex
No function ID 		No Function Id
A gene review exists, but this function lacks a GO identifier. Free-text chemistry is not automatically compared.
mouse_syk_kinase Syk
UniProtKB:P48025
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).
mouse_btk_kinase Btk
UniProtKB:P35991
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).
mouse_blnk_adaptor Blnk
UniProtKB:Q9QUN3
Gene 		signaling adaptor activity
GO:0035591 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mouse_plcg2_plc Plcg2
UniProtKB:Q8CIH5
Gene 		phosphatidylinositol-4,5-bisphosphate phospholipase C activity
GO:0004435 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mouse_pik3cd_pi3k Pik3cd
UniProtKB:O35904
Gene 		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).
chick_syk_kinase SYK
UniProtKB:F1N9Y5
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).
chick_btk_kinase BTK
UniProtKB:Q8JH64
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).
chick_blnk_adaptor BLNK
UniProtKB:Q9YGC1
Gene 		signaling adaptor activity
GO:0035591 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
human_pik3cg_pi3k PIK3CG
UniProtKB:P48736
Gene 		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).
human_cd79a_unit CD79A classification
PANTHER:PTHR14334:SF1
Family 		signaling receptor complex adaptor activity
GO:0030159 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR14334:SF1.
human_cd79b_unit CD79B classification
PANTHER:PTHR14334:SF2
Family 		contribution to signaling by the BCR complex
No function ID 		No Function Id
The family function has no GO identifier for comparison; prose is not matched.
human_syk_kinase SYK classification
PANTHER:PTHR24418
Family 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24418.
human_blnk_adaptor BLNK classification
PANTHER:PTHR14098:SF3
Family 		signaling adaptor activity
GO:0035591 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR14098:SF3.
human_p110delta_unit PIK3CD classification
PANTHER:PTHR10048:SF35
Family 		1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
GO:0046934 		Family Supported
Family review supports GO:0046934 for PANTHER:PTHR10048:SF35. Only the class I PI3K catalytic subunits (alpha SF107, beta SF33, gamma SF34, delta SF35). The kit_signaling module asserts this activity on the base family, which is too broad: it would include VPS34 and the PI4Ks.
human_p85alpha_unit PIK3R1 classification
PANTHER:PTHR10155:SF3
Family 		1-phosphatidylinositol-3-kinase regulator activity
GO:0046935 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10155:SF3.
human_btk_pip3_binding BTK classification
PANTHER:PTHR24418
Family 		phosphatidylinositol-3,4,5-trisphosphate binding
GO:0005547 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24418.
human_btk_kinase BTK classification
PANTHER:PTHR24418
Family 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24418.
human_plcg2_plc PLCG2 classification
PANTHER:PTHR10336:SF25
Family 		phosphatidylinositol-4,5-bisphosphate phospholipase C activity
GO:0004435 		Family Supported
Family review supports GO:0004435 FAMILY_WIDE. Every reviewed member (fungal PLC1/plc1, PLCG1, PLCG2) accepts it. fgfr_signaling selects SF173 (PLCG1) and myo_inositol_and_inositol_phosphate_biosynthesis selects SF36 (fungal PLC).
human_cd19_receptor_adaptor CD19 classification
PANTHER:PTHR16674:SF2
Family 		signaling receptor complex adaptor activity
GO:0030159 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR16674:SF2.
human_pik3ap1_p85_binding PIK3AP1 classification
PANTHER:PTHR16267:SF12
Family 		phosphatidylinositol 3-kinase regulatory subunit binding
GO:0036312 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR16267:SF12.
human_lyn_kinase LYN classification
PANTHER:PTHR24418
Family 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24418.
mouse_cd79a_unit Cd79a classification
PANTHER:PTHR14334:SF1
Family 		signaling receptor complex adaptor activity
GO:0030159 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR14334:SF1.
mouse_cd79b_unit Cd79b classification
PANTHER:PTHR14334:SF2
Family 		contribution to signaling by the BCR complex
No function ID 		No Function Id
The family function has no GO identifier for comparison; prose is not matched.
mouse_syk_kinase Syk classification
PANTHER:PTHR24418
Family 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24418.
mouse_btk_kinase Btk classification
PANTHER:PTHR24418
Family 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24418.
mouse_blnk_adaptor Blnk classification
PANTHER:PTHR14098:SF3
Family 		signaling adaptor activity
GO:0035591 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR14098:SF3.
mouse_plcg2_plc Plcg2 classification
PANTHER:PTHR10336:SF25
Family 		phosphatidylinositol-4,5-bisphosphate phospholipase C activity
GO:0004435 		Family Supported
Family review supports GO:0004435 FAMILY_WIDE. Every reviewed member (fungal PLC1/plc1, PLCG1, PLCG2) accepts it. fgfr_signaling selects SF173 (PLCG1) and myo_inositol_and_inositol_phosphate_biosynthesis selects SF36 (fungal PLC).
mouse_pik3cd_pi3k Pik3cd classification
PANTHER:PTHR10048:SF35
Family 		1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
GO:0046934 		Family Supported
Family review supports GO:0046934 for PANTHER:PTHR10048:SF35. Only the class I PI3K catalytic subunits (alpha SF107, beta SF33, gamma SF34, delta SF35). The kit_signaling module asserts this activity on the base family, which is too broad: it would include VPS34 and the PI4Ks.
chick_syk_kinase SYK classification
PANTHER:PTHR24418
Family 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24418.
chick_btk_kinase BTK classification
PANTHER:PTHR24418
Family 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24418.
chick_blnk_adaptor BLNK classification
PANTHER:PTHR14098:SF3
Family 		signaling adaptor activity
GO:0035591 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR14098:SF3.
human_pik3cg_pi3k PIK3CG classification
PANTHER:PTHR10048:SF34
Family 		1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
GO:0046934 		Family Supported
Family review supports GO:0046934 for PANTHER:PTHR10048:SF34. Only the class I PI3K catalytic subunits (alpha SF107, beta SF33, gamma SF34, delta SF35). The kit_signaling module asserts this activity on the base family, which is too broad: it would include VPS34 and the PI4Ks.

Gene-review completeness (22/22 grounded genes reviewed)

5 complete review(s) · 4 with deep research · 0 missing review · 18 reviewed but lacking deep research

Gene Review Complete Deep research
BLNK Q8WV28 ✓ 40/45 ✗
Blnk Q9QUN3 ✓ 35/38 ✗
BLNK Q9YGC1 ✓ 13/14 ✗
Btk P35991 ✓ 98/121 ✗
BTK Q06187 ✓ 135/149 ✗
BTK Q8JH64 ✓ 20/21 ✗
CD19 P15391 ✓ ✓ ✗
Cd79a P11911 ✓ ✓ ✗
CD79A P11912 ✓ ✓ ✗
Cd79b P15530 ✓ 30/31 ✗
CD79B P40259 ✓ ✓ ✗
LYN P07948 ✓ 316/320 ✓
PIK3AP1 Q6ZUJ8 ✓ ✓ ✗
PIK3CD O00329 ✓ 112/114 ✓
Pik3cd O35904 ✓ 48/50 ✗
PIK3CG P48736 ✓ 99/102 ✗
PIK3R1 P27986 ✓ 413/415 ✓
PLCG2 P16885 ✓ 176/178 ✗
Plcg2 Q8CIH5 ✓ 136/141 ✗
SYK F1N9Y5 ✓ 44/47 ✗
SYK P43405 ✓ 264/278 ✗
Syk P48025 ✓ 216/225 ✓

Details

Context
Homo sapiensNCBITaxon:9606 Mus musculusNCBITaxon:10090 Gallus gallusNCBITaxon:9031
plasma membraneGO:0005886 cytosolGO:0005829
Antigen-engaged membrane immunoglobulin with intact CD79 signaling subunits

Root taxa describe sampled evidence. Required roles use a human reference implementation; optional mouse/chicken segments are incomplete comparisons and do not substitute across species.

Proximal antigen-triggered BCR signalingSignaling Pathwayb_cell_receptor_signaling
B cell receptor signaling pathwayGO:0050853
Context
Homo sapiensNCBITaxon:9606 Mus musculusNCBITaxon:10090 Gallus gallusNCBITaxon:9031
plasma membraneGO:0005886 cytosolGO:0005829
Antigen-engaged membrane immunoglobulin with intact CD79 signaling subunits

Root taxa describe sampled evidence. Required roles use a human reference implementation; optional mouse/chicken segments are incomplete comparisons and do not substitute across species.

Connections

Phosphorylated CD79 ITAMs recruit SYK through tandem SH2 recognition, allowing kinase activation; the initiating ligand-bound immunoglobulin is boundary input.
Context
Homo sapiensNCBITaxon:9606
PMID:24167721
B lymphocyte antigen receptor signaling: initiation, amplification, and regulation.
Phosphorylated CD79 ITAMs recruit SYK through tandem SH2 recognition.
Dual phosphorylation of ITAM tyrosines leads to Syk binding via its tandem SH2 domains
PMID:38203179
B-Cell Receptor Signaling and Beyond: The Role of Igα (CD79a)/Igβ (CD79b) in Normal and Malignant B Cells.
CD79 chains combine receptor assembly, ITAM signaling and non-ITAM recruitment roles. Mouse CD79a Y204 is highlighted for BLNK recruitment; do not transpose residue numbering to human.
mCD79a Y204 phosphorylation is of particular importance for BLNK recruitment.
LYN can phosphorylate the CD79A ITAM. This is a context-dependent activating contribution, not a unique obligatory initiator.
Context
Homo sapiensNCBITaxon:9606
PMID:10748115
Substrate recognition by the Lyn protein-tyrosine kinase. NMR structure of the immunoreceptor tyrosine-based activation motif signaling region of the B cell antigen receptor.
LYN can phosphorylate the CD79A ITAM, providing an activating input into receptor signaling; this does not make LYN the sole initiating kinase.
phosphorylation of the CD79a (Ig-alpha) ITAM by Lyn
PMID:8137818
Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+ mobilization through distinct pathways.
LYN and SYK loss have different calcium/IP3 effects. LYN is not modeled as the uniquely indispensable kinase for all activated BCR routes.
Lyn-deficient cells evoked a delayed and slow Ca2+ mobilization, despite the normal kinetics of IP3 turnover.
human_syk_kinase -> human_blnk_adaptor Positively Regulates
SYK phosphorylates BLNK, generating effector docking sites; the purified comparison separates scaffold phosphorylation from efficient direct PLCG2 phosphorylation.
Context
Homo sapiensNCBITaxon:9606
PMID:11606584
Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling.
Purified BTK phosphorylates PLCG2 efficiently, whereas SYK preferentially phosphorylates BLNK; human PLCG2 rescue in chicken DT40 cells separates construct identity from host species.
Btk had much greater ability to phosphorylate recombinant PLCgamma2 in vitro, whereas Syk efficiently phosphorylated adapter protein BLNK.
human_blnk_adaptor -> human_btk_kinase Provides Input For
The phosphorylated scaffold organizes BTK and PLCG2 in the same signalosome; this relationship is organizing activity, not BLNK catalysis.
Context
Homo sapiensNCBITaxon:9606
PMID:12456653
BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins.
Multiple human BLNK phosphotyrosines organize different effectors in cis, supporting scaffold activity rather than generic binding or a fixed unverified stoichiometry.
phosphorylation of five tyrosine residues within human BLNK nucleates distinct signaling effectors
PMID:24167721
B lymphocyte antigen receptor signaling: initiation, amplification, and regulation.
Phosphorylated BLNK assembles BTK and PLCG2 effectors.
Phospho-Blnk serves as a scaffold for the assembly of the other components, including Bruton’s tyrosine kinase (Btk), Vav 1, and phospholipase C-gamma 2 (PLCγ2)
human_blnk_adaptor -> human_plcg2_plc Provides Input For
BLNK phosphotyrosines recruit PLCG2 into a productive assembly.
Context
Homo sapiensNCBITaxon:9606
PMID:11606584
Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling.
Purified BTK phosphorylates PLCG2 efficiently, whereas SYK preferentially phosphorylates BLNK; human PLCG2 rescue in chicken DT40 cells separates construct identity from host species.
Btk had much greater ability to phosphorylate recombinant PLCgamma2 in vitro, whereas Syk efficiently phosphorylated adapter protein BLNK.
PMID:12456653
BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins.
Multiple human BLNK phosphotyrosines organize different effectors in cis, supporting scaffold activity rather than generic binding or a fixed unverified stoichiometry.
phosphorylation of five tyrosine residues within human BLNK nucleates distinct signaling effectors
PMID:24167721
B lymphocyte antigen receptor signaling: initiation, amplification, and regulation.
Phosphorylated BLNK assembles BTK and PLCG2 effectors.
Phospho-Blnk serves as a scaffold for the assembly of the other components, including Bruton’s tyrosine kinase (Btk), Vav 1, and phospholipase C-gamma 2 (PLCγ2)
PIP3 generated by class IA PI3K is recognized by the BTK PH domain. Mouse genetic/acute-inhibitor evidence supports the pathway order; human domain/enzyme assays supply the molecular activities.
Context
Homo sapiensNCBITaxon:9606
PMID:12235209
A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation.
Native mouse p110-delta loss impairs BTK/PLCG2 activation and calcium signaling, supporting the PI3K contribution upstream of this branch.
p110delta function is required for BCR-mediated calcium flux, activation of phosphlipaseCgamma2, and Bruton's tyrosine kinase.
PMID:16179367
Key role of the p110delta isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110delta function in B cells.
Acute isoform-selective inhibition reproduces the mouse genetic BCR defect, reducing the risk of assigning a purely developmental consequence as proximal signaling.
a p110delta-selective small molecule inhibitor mirrors the effect of genetic inactivation of p110delta in BCR signaling.
PMID:17823121
Mechanistic basis of differential cellular responses of phosphatidylinositol 3,4-bisphosphate- and phosphatidylinositol 3,4,5-trisphosphate-binding pleckstrin homology domains.
BTK PH-domain recognition of PIP3 supplies the molecular link between class IA lipid production and membrane recruitment.
Btk-PH and TAPP1-PH showed genuine PtdIns(3,4,5)P3 and PtdIns(3,4)P2 specificities, respectively
human_btk_pip3_binding -> human_btk_kinase Positively Regulates
PIP3 binding promotes membrane recruitment and access to the signaling assembly; recruitment alone is not treated as sufficient for every activation step.
Context
Homo sapiensNCBITaxon:9606
PMID:17823121
Mechanistic basis of differential cellular responses of phosphatidylinositol 3,4-bisphosphate- and phosphatidylinositol 3,4,5-trisphosphate-binding pleckstrin homology domains.
BTK PH-domain recognition of PIP3 supplies the molecular link between class IA lipid production and membrane recruitment.
Btk-PH and TAPP1-PH showed genuine PtdIns(3,4,5)P3 and PtdIns(3,4)P2 specificities, respectively
PMID:39917832
Signaling Activation and Modulation in Extrafollicular B Cell Responses.
PI3K lipid production recruits PH-domain effectors before the BTK/PLCG2 output step. Downstream extrafollicular fate decisions integrate other receptors and are outside the proximal module.
production results in the recruitment of BTK and AKT to the plasma membrane
human_btk_kinase -> human_plcg2_plc Positively Regulates
BTK efficiently phosphorylates PLCG2 in vitro; human PLCG2 rescue in DT40 links its phosphorylatable sites to BCR calcium responses.
Context
Homo sapiensNCBITaxon:9606
PMID:11606584
Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling.
Purified BTK phosphorylates PLCG2 efficiently, whereas SYK preferentially phosphorylates BLNK; human PLCG2 rescue in chicken DT40 cells separates construct identity from host species.
Btk had much greater ability to phosphorylate recombinant PLCgamma2 in vitro, whereas Syk efficiently phosphorylated adapter protein BLNK.
PMID:8691147
A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2.
BTK loss in DT40 reduces PLCG2 phosphorylation and eliminates the measured phosphoinositide/calcium response. BTK and SYK act together; direct substrate chemistry requires more than this knockout.
PLC-gamma 2 activation is regulated by Btk and Syk through their concerted actions.
PMID:15509800
Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2.
Human Ramos and native mouse splenic B cells show BCR-linked PLCG2 phosphorylation. BTK inhibitor/RNA-interference experiments were performed in Ramos cells and support a major, incomplete contribution to phosphorylation of the activating sites; they are not native mouse BTK knockouts.
Examination of the effects of various pharmacological inhibitors and of RNA interference in Ramos cells suggested that Btk is largely, but not completely, responsible for phosphorylation of Y753 and Y759, whereas phosphorylation of Y1217 is independent of Btk.
Phosphorylated CD19 provides a p85 recruitment route; its quantitative requirement depends on the complementary adaptor context.
Context
Homo sapiensNCBITaxon:9606
PMID:9382888
Qualitative regulation of B cell antigen receptor signaling by CD19: selective requirement for PI3-kinase activation, inositol-1,4,5-trisphosphate production and Ca2+ mobilization.
CD19 couples receptor stimulation to PI3K activation through phosphorylated cytoplasmic docking sites. Its requirement is contextual and considered alongside complementary BCAP recruitment.
PI3-Kinase activation is dependent on phosphorylation of CD19 Y484 and Y515.
PMID:18025150
Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase.
CD19 and BCAP complement each other in mouse BCR-mediated PI3K activation. Encode recruitment alternatives rather than two universal independent requirements.
BCAP and CD19 have complementary roles in BCR-mediated PI3K activation
Human phosphorylated BCAP binds p85 SH2 domains. Mouse CD19/BCAP genetics establishes complementary recruitment in native BCR signaling.
Context
Homo sapiensNCBITaxon:9606
PMID:31527084
Phosphorylation of the multifunctional signal transducer B-cell adaptor protein (BCAP) promotes recruitment of multiple SH2/SH3 proteins including GRB2.
Human BCAP binds p85 SH2 domains through phosphorylated YXXM motifs. BTK phosphorylates purified BCAP more efficiently than SYK or LYN in the reported assay, supporting a potential feedback connection.
the p85 SH2 domain binds to the three C-terminal YXXM in BCAP
PMID:18025150
Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase.
CD19 and BCAP complement each other in mouse BCR-mediated PI3K activation. Encode recruitment alternatives rather than two universal independent requirements.
BCAP and CD19 have complementary roles in BCR-mediated PI3K activation
Purified SYK can phosphorylate BCAP, with substantially lower activity than BTK in the reported assay. The edge represents biochemical capacity rather than a universal rate-limiting native step.
Context
Homo sapiensNCBITaxon:9606
PMID:31527084
Phosphorylation of the multifunctional signal transducer B-cell adaptor protein (BCAP) promotes recruitment of multiple SH2/SH3 proteins including GRB2.
Purified BTK, SYK and LYN phosphorylate BCAP with different efficiencies in the reported biochemical assay.
nonreceptor tyrosine kinases SYK, LYN, and BTK were able to phosphorylate BCAP, but BTK is by far the most efficient
BTK phosphorylates BCAP in the purified assay, supplying a possible reinforcing route to p85 recruitment. A complete native feedback kinetic cycle has not been established.
Context
Homo sapiensNCBITaxon:9606
PMID:31527084
Phosphorylation of the multifunctional signal transducer B-cell adaptor protein (BCAP) promotes recruitment of multiple SH2/SH3 proteins including GRB2.
Purified BTK, SYK and LYN phosphorylate BCAP with different efficiencies in the reported biochemical assay.
nonreceptor tyrosine kinases SYK, LYN, and BTK were able to phosphorylate BCAP, but BTK is by far the most efficient
Part: ITAM-bearing receptor signaling assembly
CD79 signaling-subunit assemblyRegulatory Stephuman_cd79_step

The receptor is already antigen engaged. CD79 tails recruit signaling machinery after phosphorylation; CD79 is not itself the antigen-recognition component.

Context
Homo sapiensNCBITaxon:9606
PMID:38203179
B-Cell Receptor Signaling and Beyond: The Role of Igα (CD79a)/Igβ (CD79b) in Normal and Malignant B Cells.
CD79 chains combine receptor assembly, ITAM signaling and non-ITAM recruitment roles. Mouse CD79a Y204 is highlighted for BLNK recruitment; do not transpose residue numbering to human.
mCD79a Y204 phosphorylation is of particular importance for BLNK recruitment.

Annotons

CD79A/CD79B signaling assembly
human_cd79_signaling_assembly
Participant: Protein Complex: CD79A/CD79B heterodimer within an engaged BCR
Protein Complex:
CD79A/CD79B heterodimer within an engaged BCR The engaged membrane-immunoglobulin component supplies antigen recognition and is an upstream context. The modeled units are its CD79 signaling subunits, not a complete isolated antigen-binding receptor.
Active units:
CD79A1
Participant: Gene Product: CD79A
Gene Product:
CD79AUniProtKB:P11912
Family:
CD79A classificationPANTHER:PTHR14334:SF1 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: CD79AUniProtKB:P11912
Taxon:
Homo sapiensNCBITaxon:9606
Role: ITAM-bearing signal-transducing subunit
Function:
signaling receptor complex adaptor activityGO:0030159
CD79B1
Participant: Gene Product: CD79B
Gene Product:
CD79BUniProtKB:P40259
Family:
CD79B classificationPANTHER:PTHR14334:SF2 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: CD79BUniProtKB:P40259
Taxon:
Homo sapiensNCBITaxon:9606
Role: ITAM-bearing signal-transducing subunit
Function:
contribution to signaling by the BCR complex CD79B contributes to receptor-complex activity. It is not an autonomous antigen-binding receptor or a kinase.
Taxon:
Homo sapiensNCBITaxon:9606

Function

ITAM-dependent signal transduction by the CD79 assembly The tandem signaling tails supply phosphotyrosine docking sites. No autonomous transmembrane receptor activity is assigned to either isolated subunit.

Signal transduction downstream of antigen-engaged membrane immunoglobulin. Triggering geometry and isotype-specific thresholds remain outside this step.

PMID:38203179
B-Cell Receptor Signaling and Beyond: The Role of Igα (CD79a)/Igβ (CD79b) in Normal and Malignant B Cells.
CD79 chains combine receptor assembly, ITAM signaling and non-ITAM recruitment roles. Mouse CD79a Y204 is highlighted for BLNK recruitment; do not transpose residue numbering to human.
mCD79a Y204 phosphorylation is of particular importance for BLNK recruitment.
PMID:35981043
Cryo-EM structure of the human IgM B cell receptor.
Resting human IgM BCR contains membrane immunoglobulin plus one CD79 heterodimer. CD79 alone is not the antigen-recognition unit.
IgM-BCR comprises two heavy chains, two light chains, and the Igα/Igβ heterodimer.
Part: SYK kinase input
SYK kinase inputRegulatory Stephuman_syk_kinase_step

phosphotyrosine signaling and BLNK phosphorylation

Context
Homo sapiensNCBITaxon:9606
PMID:11606584
Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling.
Purified BTK phosphorylates PLCG2 efficiently, whereas SYK preferentially phosphorylates BLNK; human PLCG2 rescue in chicken DT40 cells separates construct identity from host species.
Btk had much greater ability to phosphorylate recombinant PLCgamma2 in vitro, whereas Syk efficiently phosphorylated adapter protein BLNK.

Annotons

SYK: phosphotyrosine signaling and BLNK phosphorylation
human_syk_kinase
Participant: Gene Product: SYK
Gene Product:
SYKUniProtKB:P43405
Family:
SYK classificationPANTHER:PTHR24418 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: SYKUniProtKB:P43405
Taxon:
Homo sapiensNCBITaxon:9606

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

phosphotyrosine signaling and BLNK phosphorylation

PMID:24167721
B lymphocyte antigen receptor signaling: initiation, amplification, and regulation.
BLNK is a phosphotyrosine scaffold connecting kinase activity to effector recruitment. LYN also has inhibitory roles and CD19/BCAP contributions vary with stimulus; a rigid linear kinase chain is insufficient.
Phospho-Blnk serves as a scaffold for the assembly of the other components
PMID:11606584
Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling.
Purified BTK phosphorylates PLCG2 efficiently, whereas SYK preferentially phosphorylates BLNK; human PLCG2 rescue in chicken DT40 cells separates construct identity from host species.
Btk had much greater ability to phosphorylate recombinant PLCgamma2 in vitro, whereas Syk efficiently phosphorylated adapter protein BLNK.
Part: BLNK signaling scaffold
BLNK signaling scaffoldRegulatory Stephuman_blnk_adaptor_step

phosphorylation-dependent assembly of kinase and PLC effectors

Context
Homo sapiensNCBITaxon:9606
PMID:12456653
BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins.
Multiple human BLNK phosphotyrosines organize different effectors in cis, supporting scaffold activity rather than generic binding or a fixed unverified stoichiometry.
phosphorylation of five tyrosine residues within human BLNK nucleates distinct signaling effectors

Annotons

BLNK: phosphorylation-dependent assembly of kinase and PLC effectors
human_blnk_adaptor
Participant: Gene Product: BLNK
Gene Product:
BLNKUniProtKB:Q8WV28
Family:
BLNK classificationPANTHER:PTHR14098:SF3 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: BLNKUniProtKB:Q8WV28
Taxon:
Homo sapiensNCBITaxon:9606

Function

signaling adaptor activityGO:0035591

phosphorylation-dependent assembly of kinase and PLC effectors

PMID:12456653
BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins.
Multiple human BLNK phosphotyrosines organize different effectors in cis, supporting scaffold activity rather than generic binding or a fixed unverified stoichiometry.
phosphorylation of five tyrosine residues within human BLNK nucleates distinct signaling effectors
PMID:11606584
Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling.
Purified BTK phosphorylates PLCG2 efficiently, whereas SYK preferentially phosphorylates BLNK; human PLCG2 rescue in chicken DT40 cells separates construct identity from host species.
Btk had much greater ability to phosphorylate recombinant PLCgamma2 in vitro, whereas Syk efficiently phosphorylated adapter protein BLNK.
Part: PIP3 production by a class IA assembly
Class IA PIP3 productionRegulatory Stephuman_class_ia_pi3k_step

PIP3 formation supplies a recruitment signal upstream of the BTK/PLCG2 branch; it is not a terminal output of a strictly linear SYK-BTK sequence.

Context
Homo sapiensNCBITaxon:9606
PMID:15135396
Cloning, expression, purification, and characterization of the human Class Ia phosphoinositide 3-kinase isoforms.
Human p110-delta and p85-alpha form an experimentally characterized class IA lipid-kinase assembly; p85 is regulatory and p110 performs lipid phosphorylation.
the three human Class Ia PI3K (alpha, beta, and delta) p110 catalytic domains were cloned and co-expressed with the p85alpha regulatory domain in Sf9 cells.
PMID:12235209
A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation.
Native mouse p110-delta loss impairs BTK/PLCG2 activation and calcium signaling, supporting the PI3K contribution upstream of this branch.
p110delta function is required for BCR-mediated calcium flux, activation of phosphlipaseCgamma2, and Bruton's tyrosine kinase.

Annotons

p85-alpha/p110-delta class IA PI3K
human_class_ia_pi3k
Participant: Protein Complex: p85-alpha/p110-delta class IA PI3K
Protein Complex:
p85-alpha/p110-delta class IA PI3KGO:0005943
Active units:
p110-delta1
Participant: Gene Product: PIK3CD
Gene Product:
PIK3CDUniProtKB:O00329
Family:
PIK3CD classificationPANTHER:PTHR10048:SF35 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: PIK3CDUniProtKB:O00329
Taxon:
Homo sapiensNCBITaxon:9606
Role: lipid phosphorylation
Function:
1-phosphatidylinositol-4,5-bisphosphate 3-kinase activityGO:0046934
p85-alpha1
Participant: Gene Product: PIK3R1
Gene Product:
PIK3R1UniProtKB:P27986
Family:
PIK3R1 classificationPANTHER:PTHR10155:SF3 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: PIK3R1UniProtKB:P27986
Taxon:
Homo sapiensNCBITaxon:9606
Role: regulation and phosphotyrosine-dependent recruitment
Function:
1-phosphatidylinositol-3-kinase regulator activityGO:0046935
Taxon:
Homo sapiensNCBITaxon:9606

Function

1-phosphatidylinositol-4,5-bisphosphate 3-kinase activityGO:0046934
Substrates: phosphatidylinositol 4,5-bisphosphate (PIP2) ATP
Products: phosphatidylinositol 3,4,5-trisphosphate (PIP3) ADP

Human reference class IA assembly converts membrane PIP2 into PIP3. p85-alpha regulates and recruits the enzyme; p110-delta performs lipid catalysis. Other regulatory isoforms and tonic alpha/delta compensation are outside this concrete implementation.

PMID:15135396
Cloning, expression, purification, and characterization of the human Class Ia phosphoinositide 3-kinase isoforms.
Human p110-delta and p85-alpha form an experimentally characterized class IA lipid-kinase assembly; p85 is regulatory and p110 performs lipid phosphorylation.
the three human Class Ia PI3K (alpha, beta, and delta) p110 catalytic domains were cloned and co-expressed with the p85alpha regulatory domain in Sf9 cells.
PMID:12235209
A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation.
Native mouse p110-delta loss impairs BTK/PLCG2 activation and calcium signaling, supporting the PI3K contribution upstream of this branch.
p110delta function is required for BCR-mediated calcium flux, activation of phosphlipaseCgamma2, and Bruton's tyrosine kinase.
PMID:20699475
The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development.
Mouse alpha/delta compensation concerns tonic signaling; the assayed antigen-triggered response instead depends on delta. Limit isoform specificity to the tested boundary.
Unlike p110delta, however, p110alpha did not contribute to agonist-induced BCR signaling.
Part: BTK kinase and lipid-dependent recruitment
BTK kinase and lipid-dependent recruitmentRegulatory Stephuman_btk_kinase_step

PLCG2 phosphorylation

Context
Homo sapiensNCBITaxon:9606
PMID:11606584
Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling.
Purified BTK phosphorylates PLCG2 efficiently, whereas SYK preferentially phosphorylates BLNK; human PLCG2 rescue in chicken DT40 cells separates construct identity from host species.
Btk had much greater ability to phosphorylate recombinant PLCgamma2 in vitro, whereas Syk efficiently phosphorylated adapter protein BLNK.
PMID:17823121
Mechanistic basis of differential cellular responses of phosphatidylinositol 3,4-bisphosphate- and phosphatidylinositol 3,4,5-trisphosphate-binding pleckstrin homology domains.
BTK PH-domain recognition of PIP3 supplies the molecular link between class IA lipid production and membrane recruitment.
Btk-PH and TAPP1-PH showed genuine PtdIns(3,4,5)P3 and PtdIns(3,4)P2 specificities, respectively

Annotons

BTK: PIP3-dependent membrane recruitment
human_btk_pip3_binding
Participant: Gene Product: BTK
Gene Product:
BTKUniProtKB:Q06187
Family:
BTK classificationPANTHER:PTHR24418 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: BTKUniProtKB:Q06187
Taxon:
Homo sapiensNCBITaxon:9606

Function

phosphatidylinositol-3,4,5-trisphosphate bindingGO:0005547

PIP3-dependent membrane recruitment

PMID:17823121
Mechanistic basis of differential cellular responses of phosphatidylinositol 3,4-bisphosphate- and phosphatidylinositol 3,4,5-trisphosphate-binding pleckstrin homology domains.
BTK PH-domain recognition of PIP3 supplies the molecular link between class IA lipid production and membrane recruitment.
Btk-PH and TAPP1-PH showed genuine PtdIns(3,4,5)P3 and PtdIns(3,4)P2 specificities, respectively
PMID:39917832
Signaling Activation and Modulation in Extrafollicular B Cell Responses.
PI3K lipid production recruits PH-domain effectors before the BTK/PLCG2 output step. Downstream extrafollicular fate decisions integrate other receptors and are outside the proximal module.
production results in the recruitment of BTK and AKT to the plasma membrane
BTK: PLCG2 phosphorylation
human_btk_kinase
Participant: Gene Product: BTK
Gene Product:
BTKUniProtKB:Q06187
Family:
BTK classificationPANTHER:PTHR24418 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: BTKUniProtKB:Q06187
Taxon:
Homo sapiensNCBITaxon:9606

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

PLCG2 phosphorylation

PMID:11606584
Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling.
Purified BTK phosphorylates PLCG2 efficiently, whereas SYK preferentially phosphorylates BLNK; human PLCG2 rescue in chicken DT40 cells separates construct identity from host species.
Btk had much greater ability to phosphorylate recombinant PLCgamma2 in vitro, whereas Syk efficiently phosphorylated adapter protein BLNK.
PMID:8691147
A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2.
BTK loss in DT40 reduces PLCG2 phosphorylation and eliminates the measured phosphoinositide/calcium response. BTK and SYK act together; direct substrate chemistry requires more than this knockout.
PLC-gamma 2 activation is regulated by Btk and Syk through their concerted actions.
Part: PLCG2 second-messenger production
PLCG2 second-messenger productionRegulatory Stephuman_plcg2_plc_step

PIP2 hydrolysis to IP3 and DAG

Context
Homo sapiensNCBITaxon:9606
PMID:11606584
Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling.
Purified BTK phosphorylates PLCG2 efficiently, whereas SYK preferentially phosphorylates BLNK; human PLCG2 rescue in chicken DT40 cells separates construct identity from host species.
Btk had much greater ability to phosphorylate recombinant PLCgamma2 in vitro, whereas Syk efficiently phosphorylated adapter protein BLNK.

Annotons

PLCG2: PIP2 hydrolysis to IP3 and DAG
human_plcg2_plc
Participant: Gene Product: PLCG2
Gene Product:
PLCG2UniProtKB:P16885
Family:
PLCG2 classificationPANTHER:PTHR10336:SF25 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: PLCG2UniProtKB:P16885
Taxon:
Homo sapiensNCBITaxon:9606

Function

phosphatidylinositol-4,5-bisphosphate phospholipase C activityGO:0004435
Substrates: phosphatidylinositol 4,5-bisphosphate (PIP2)
Products: inositol 1,4,5-trisphosphate (IP3) diacylglycerol (DAG)

PIP2 hydrolysis to IP3 and DAG

PMID:11606584
Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling.
Purified BTK phosphorylates PLCG2 efficiently, whereas SYK preferentially phosphorylates BLNK; human PLCG2 rescue in chicken DT40 cells separates construct identity from host species.
Btk had much greater ability to phosphorylate recombinant PLCgamma2 in vitro, whereas Syk efficiently phosphorylated adapter protein BLNK.
PMID:24167721
B lymphocyte antigen receptor signaling: initiation, amplification, and regulation.
BLNK is a phosphotyrosine scaffold connecting kinase activity to effector recruitment. LYN also has inhibitory roles and CD19/BCAP contributions vary with stimulus; a rigid linear kinase chain is insufficient.
Phospho-Blnk serves as a scaffold for the assembly of the other components
PMID:11043765
Regulation of the phospholipase C-gamma2 pathway in B cells.
The reviewed PLCG2 reaction hydrolyses PIP2 to lipid second messengers; IP3 acts on a separate ER channel. This is pathway/chemistry synthesis across experimental systems, not a new native-species enzyme assay.
The activated PLC-gamma2 converts phosphatidylinositol 4,5-bisphosphate into the second messenger inositol 1,4,5-trisphosphate (IP3), which in turn binds to IP3 receptors located on the endoplasmic reticulum (ER).
Part: CD19: receptor-associated recruitment of PI3K (optional)
CD19: receptor-associated recruitment of PI3KRegulatory Stephuman_cd19_receptor_adaptor_step

CD19 provides an accessory recruitment route; BCAP and other receptor-associated signals can complement it.

Context
Homo sapiensNCBITaxon:9606
PMID:9382888
Qualitative regulation of B cell antigen receptor signaling by CD19: selective requirement for PI3-kinase activation, inositol-1,4,5-trisphosphate production and Ca2+ mobilization.
CD19 couples receptor stimulation to PI3K activation through phosphorylated cytoplasmic docking sites. Its requirement is contextual and considered alongside complementary BCAP recruitment.
PI3-Kinase activation is dependent on phosphorylation of CD19 Y484 and Y515.
PMID:18025150
Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase.
CD19 and BCAP complement each other in mouse BCR-mediated PI3K activation. Encode recruitment alternatives rather than two universal independent requirements.
BCAP and CD19 have complementary roles in BCR-mediated PI3K activation

Annotons

CD19: receptor-associated recruitment of PI3K
human_cd19_receptor_adaptor
Participant: Gene Product: CD19
Gene Product:
CD19UniProtKB:P15391
Family:
CD19 classificationPANTHER:PTHR16674:SF2 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: CD19UniProtKB:P15391
Taxon:
Homo sapiensNCBITaxon:9606

Function

signaling receptor complex adaptor activityGO:0030159

receptor-associated recruitment of PI3K

PMID:9382888
Qualitative regulation of B cell antigen receptor signaling by CD19: selective requirement for PI3-kinase activation, inositol-1,4,5-trisphosphate production and Ca2+ mobilization.
CD19 couples receptor stimulation to PI3K activation through phosphorylated cytoplasmic docking sites. Its requirement is contextual and considered alongside complementary BCAP recruitment.
PI3-Kinase activation is dependent on phosphorylation of CD19 Y484 and Y515.
PMID:18025150
Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase.
CD19 and BCAP complement each other in mouse BCR-mediated PI3K activation. Encode recruitment alternatives rather than two universal independent requirements.
BCAP and CD19 have complementary roles in BCR-mediated PI3K activation
Part: PIK3AP1: phosphorylation-dependent p85 recruitment (optional)
PIK3AP1: phosphorylation-dependent p85 recruitmentRegulatory Stephuman_pik3ap1_p85_binding_step

BCAP provides a complementary p85 recruitment route. CD19 and BCAP are not encoded as two universal independent requirements.

Context
Homo sapiensNCBITaxon:9606
PMID:31527084
Phosphorylation of the multifunctional signal transducer B-cell adaptor protein (BCAP) promotes recruitment of multiple SH2/SH3 proteins including GRB2.
Human BCAP binds p85 SH2 domains through phosphorylated YXXM motifs. BTK phosphorylates purified BCAP more efficiently than SYK or LYN in the reported assay, supporting a potential feedback connection.
the p85 SH2 domain binds to the three C-terminal YXXM in BCAP
PMID:18025150
Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase.
CD19 and BCAP complement each other in mouse BCR-mediated PI3K activation. Encode recruitment alternatives rather than two universal independent requirements.
BCAP and CD19 have complementary roles in BCR-mediated PI3K activation

Annotons

PIK3AP1: phosphorylation-dependent p85 recruitment
human_pik3ap1_p85_binding
Participant: Gene Product: PIK3AP1
Gene Product:
PIK3AP1UniProtKB:Q6ZUJ8
Family:
PIK3AP1 classificationPANTHER:PTHR16267:SF12 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: PIK3AP1UniProtKB:Q6ZUJ8
Taxon:
Homo sapiensNCBITaxon:9606

Function

phosphatidylinositol 3-kinase regulatory subunit bindingGO:0036312

phosphorylation-dependent p85 recruitment

PMID:31527084
Phosphorylation of the multifunctional signal transducer B-cell adaptor protein (BCAP) promotes recruitment of multiple SH2/SH3 proteins including GRB2.
Human BCAP binds p85 SH2 domains through phosphorylated YXXM motifs. BTK phosphorylates purified BCAP more efficiently than SYK or LYN in the reported assay, supporting a potential feedback connection.
the p85 SH2 domain binds to the three C-terminal YXXM in BCAP
PMID:18025150
Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase.
CD19 and BCAP complement each other in mouse BCR-mediated PI3K activation. Encode recruitment alternatives rather than two universal independent requirements.
BCAP and CD19 have complementary roles in BCR-mediated PI3K activation
Part: LYN: context-dependent ITAM phosphorylation (optional)
LYN: context-dependent ITAM phosphorylationRegulatory Stephuman_lyn_kinase_step

LYN accelerates activating signaling but is not uniquely required in every BCR setting. Its inhibitory CD22/SHP1 branch is boundary context, not a direct inhibitory edge to PLCG2.

Context
Homo sapiensNCBITaxon:9606
PMID:10748115
Substrate recognition by the Lyn protein-tyrosine kinase. NMR structure of the immunoreceptor tyrosine-based activation motif signaling region of the B cell antigen receptor.
LYN can phosphorylate the CD79A ITAM, providing an activating input into receptor signaling; this does not make LYN the sole initiating kinase.
phosphorylation of the CD79a (Ig-alpha) ITAM by Lyn
PMID:8137818
Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+ mobilization through distinct pathways.
LYN and SYK loss have different calcium/IP3 effects. LYN is not modeled as the uniquely indispensable kinase for all activated BCR routes.
Lyn-deficient cells evoked a delayed and slow Ca2+ mobilization, despite the normal kinetics of IP3 turnover.
PMID:9480991
Inhibition of the B cell by CD22: a requirement for Lyn.
LYN also supports inhibitory CD22/SHP1 signaling in native mouse B cells; the sign of its net BCR effect depends on receptor context.
in the absence of Lyn, the ability of CD22 to become tyrosine phosphorylated after ligation of mIg, to recruit SHP-1, and to suppress mIg-induced elevation of intracellular [Ca2+] is lost.

Annotons

LYN: context-dependent ITAM phosphorylation
human_lyn_kinase
Participant: Gene Product: LYN
Gene Product:
LYNUniProtKB:P07948
Family:
LYN classificationPANTHER:PTHR24418 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: LYNUniProtKB:P07948
Taxon:
Homo sapiensNCBITaxon:9606

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

context-dependent ITAM phosphorylation

PMID:10748115
Substrate recognition by the Lyn protein-tyrosine kinase. NMR structure of the immunoreceptor tyrosine-based activation motif signaling region of the B cell antigen receptor.
LYN can phosphorylate the CD79A ITAM, providing an activating input into receptor signaling; this does not make LYN the sole initiating kinase.
phosphorylation of the CD79a (Ig-alpha) ITAM by Lyn
PMID:8137818
Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+ mobilization through distinct pathways.
LYN and SYK loss have different calcium/IP3 effects. LYN is not modeled as the uniquely indispensable kinase for all activated BCR routes.
Lyn-deficient cells evoked a delayed and slow Ca2+ mobilization, despite the normal kinetics of IP3 turnover.
PMID:9480991
Inhibition of the B cell by CD22: a requirement for Lyn.
LYN also supports inhibitory CD22/SHP1 signaling in native mouse B cells; the sign of its net BCR effect depends on receptor context.
in the absence of Lyn, the ability of CD22 to become tyrosine phosphorylated after ligation of mIg, to recruit SHP-1, and to suppress mIg-induced elevation of intracellular [Ca2+] is lost.
Part: mouse comparative evidence segment (optional)
Mouse proximal signaling comparatorsSignaling Pathwaymouse_bcr_comparative_segment

Seven reviewed mouse components substantiate native genetic and biochemical steps. Missing p85/adaptor reviews mean this is an incomplete comparator segment, not a complete alternative implementation.

Context
Mus musculusNCBITaxon:10090
PMID:12235209
A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation.
Native mouse p110-delta loss impairs BTK/PLCG2 activation and calcium signaling, supporting the PI3K contribution upstream of this branch.
p110delta function is required for BCR-mediated calcium flux, activation of phosphlipaseCgamma2, and Bruton's tyrosine kinase.
PMID:18025150
Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase.
CD19 and BCAP complement each other in mouse BCR-mediated PI3K activation. Encode recruitment alternatives rather than two universal independent requirements.
BCAP and CD19 have complementary roles in BCR-mediated PI3K activation
PMID:20699475
The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development.
Mouse alpha/delta compensation concerns tonic signaling; the assayed antigen-triggered response instead depends on delta. Limit isoform specificity to the tested boundary.
Unlike p110delta, however, p110alpha did not contribute to agonist-induced BCR signaling.
Part: mouse CD79 signaling assembly
CD79 signaling-subunit assemblyRegulatory Stepmouse_cd79_step

The receptor is already antigen engaged. CD79 tails recruit signaling machinery after phosphorylation; CD79 is not itself the antigen-recognition component.

Context
Mus musculusNCBITaxon:10090
PMID:38203179
B-Cell Receptor Signaling and Beyond: The Role of Igα (CD79a)/Igβ (CD79b) in Normal and Malignant B Cells.
CD79 chains combine receptor assembly, ITAM signaling and non-ITAM recruitment roles. Mouse CD79a Y204 is highlighted for BLNK recruitment; do not transpose residue numbering to human.
mCD79a Y204 phosphorylation is of particular importance for BLNK recruitment.

Annotons

CD79A/CD79B signaling assembly
mouse_cd79_signaling_assembly
Participant: Protein Complex: CD79A/CD79B heterodimer within an engaged BCR
Protein Complex:
CD79A/CD79B heterodimer within an engaged BCR The engaged membrane-immunoglobulin component supplies antigen recognition and is an upstream context. The modeled units are its CD79 signaling subunits, not a complete isolated antigen-binding receptor.
Active units:
Cd79a1
Participant: Gene Product: Cd79a
Gene Product:
Cd79aUniProtKB:P11911
Family:
Cd79a classificationPANTHER:PTHR14334:SF1 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: Cd79aUniProtKB:P11911
Taxon:
Mus musculusNCBITaxon:10090
Role: ITAM-bearing signal-transducing subunit
Function:
signaling receptor complex adaptor activityGO:0030159
Cd79b1
Participant: Gene Product: Cd79b
Gene Product:
Cd79bUniProtKB:P15530
Family:
Cd79b classificationPANTHER:PTHR14334:SF2 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: Cd79bUniProtKB:P15530
Taxon:
Mus musculusNCBITaxon:10090
Role: ITAM-bearing signal-transducing subunit
Function:
contribution to signaling by the BCR complex CD79B contributes to receptor-complex activity. It is not an autonomous antigen-binding receptor or a kinase.
Taxon:
Mus musculusNCBITaxon:10090

Function

ITAM-dependent signal transduction by the CD79 assembly The tandem signaling tails supply phosphotyrosine docking sites. No autonomous transmembrane receptor activity is assigned to either isolated subunit.

Signal transduction downstream of antigen-engaged membrane immunoglobulin. Triggering geometry and isotype-specific thresholds remain outside this step.

PMID:38203179
B-Cell Receptor Signaling and Beyond: The Role of Igα (CD79a)/Igβ (CD79b) in Normal and Malignant B Cells.
CD79 chains combine receptor assembly, ITAM signaling and non-ITAM recruitment roles. Mouse CD79a Y204 is highlighted for BLNK recruitment; do not transpose residue numbering to human.
mCD79a Y204 phosphorylation is of particular importance for BLNK recruitment.
PMID:24167721
B lymphocyte antigen receptor signaling: initiation, amplification, and regulation.
BLNK is a phosphotyrosine scaffold connecting kinase activity to effector recruitment. LYN also has inhibitory roles and CD19/BCAP contributions vary with stimulus; a rigid linear kinase chain is insufficient.
Phospho-Blnk serves as a scaffold for the assembly of the other components
Part: Syk comparator
Syk mouse comparatorRegulatory Stepmouse_syk_kinase_step

The individual mouse review separates native experiments from cross-species biochemical inference. This segment does not assert a complete reviewed mouse p85/adaptor implementation.

Context
Mus musculusNCBITaxon:10090
PMID:24167721
B lymphocyte antigen receptor signaling: initiation, amplification, and regulation.
BLNK is a phosphotyrosine scaffold connecting kinase activity to effector recruitment. LYN also has inhibitory roles and CD19/BCAP contributions vary with stimulus; a rigid linear kinase chain is insufficient.
Phospho-Blnk serves as a scaffold for the assembly of the other components

Annotons

Syk: comparative proximal BCR role
mouse_syk_kinase
Participant: Gene Product: Syk
Gene Product:
SykUniProtKB:P48025
Family:
Syk classificationPANTHER:PTHR24418 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: SykUniProtKB:P48025
Taxon:
Mus musculusNCBITaxon:10090

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

comparative proximal BCR role

PMID:8798454
Differential intrinsic enzymatic activity of Syk and Zap-70 protein-tyrosine kinases.
Immune-complex kinase assays establish SYK autophosphorylation and substrate tyrosine phosphorylation. The abstract does not identify the species of every construct; the mouse exemplar uses this conserved enzyme evidence together with its reviewed native signaling evidence.
the ability of Syk and SykB to undergo autophosphorylation and to phosphorylate erythrocyte band 3 in immune complex kinase reactions was at least 100-fold greater than that of Zap-70.

The individual mouse review separates native experiments from cross-species biochemical inference. This segment does not assert a complete reviewed mouse p85/adaptor implementation.

Part: Btk comparator
Btk mouse comparatorRegulatory Stepmouse_btk_kinase_step

The individual mouse review separates native experiments from cross-species biochemical inference. This segment does not assert a complete reviewed mouse p85/adaptor implementation.

Context
Mus musculusNCBITaxon:10090
PMID:8691147
A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2.
BTK loss in DT40 reduces PLCG2 phosphorylation and eliminates the measured phosphoinositide/calcium response. BTK and SYK act together; direct substrate chemistry requires more than this knockout.
PLC-gamma 2 activation is regulated by Btk and Syk through their concerted actions.
PMID:12235209
A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation.
Native mouse p110-delta loss impairs BTK/PLCG2 activation and calcium signaling, supporting the PI3K contribution upstream of this branch.
p110delta function is required for BCR-mediated calcium flux, activation of phosphlipaseCgamma2, and Bruton's tyrosine kinase.

Annotons

Btk: comparative proximal BCR role
mouse_btk_kinase
Participant: Gene Product: Btk
Gene Product:
BtkUniProtKB:P35991
Family:
Btk classificationPANTHER:PTHR24418 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: BtkUniProtKB:P35991
Taxon:
Mus musculusNCBITaxon:10090

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

comparative proximal BCR role

PMID:8691147
A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2.
BTK loss in DT40 reduces PLCG2 phosphorylation and eliminates the measured phosphoinositide/calcium response. BTK and SYK act together; direct substrate chemistry requires more than this knockout.
PLC-gamma 2 activation is regulated by Btk and Syk through their concerted actions.
PMID:12235209
A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation.
Native mouse p110-delta loss impairs BTK/PLCG2 activation and calcium signaling, supporting the PI3K contribution upstream of this branch.
p110delta function is required for BCR-mediated calcium flux, activation of phosphlipaseCgamma2, and Bruton's tyrosine kinase.
PMID:15509800
Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2.
Human Ramos and native mouse splenic B cells show BCR-linked PLCG2 phosphorylation. BTK inhibitor/RNA-interference experiments were performed in Ramos cells and support a major, incomplete contribution to phosphorylation of the activating sites; they are not native mouse BTK knockouts.
Examination of the effects of various pharmacological inhibitors and of RNA interference in Ramos cells suggested that Btk is largely, but not completely, responsible for phosphorylation of Y753 and Y759, whereas phosphorylation of Y1217 is independent of Btk.

The individual mouse review separates native experiments from cross-species biochemical inference. This segment does not assert a complete reviewed mouse p85/adaptor implementation.

Part: Blnk comparator
Blnk mouse comparatorRegulatory Stepmouse_blnk_adaptor_step

The individual mouse review separates native experiments from cross-species biochemical inference. This segment does not assert a complete reviewed mouse p85/adaptor implementation.

Context
Mus musculusNCBITaxon:10090
PMID:12456653
BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins.
Multiple human BLNK phosphotyrosines organize different effectors in cis, supporting scaffold activity rather than generic binding or a fixed unverified stoichiometry.
phosphorylation of five tyrosine residues within human BLNK nucleates distinct signaling effectors
PMID:24167721
B lymphocyte antigen receptor signaling: initiation, amplification, and regulation.
BLNK is a phosphotyrosine scaffold connecting kinase activity to effector recruitment. LYN also has inhibitory roles and CD19/BCAP contributions vary with stimulus; a rigid linear kinase chain is insufficient.
Phospho-Blnk serves as a scaffold for the assembly of the other components

Annotons

Blnk: comparative proximal BCR role
mouse_blnk_adaptor
Participant: Gene Product: Blnk
Gene Product:
BlnkUniProtKB:Q9QUN3
Family:
Blnk classificationPANTHER:PTHR14098:SF3 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: BlnkUniProtKB:Q9QUN3
Taxon:
Mus musculusNCBITaxon:10090

Function

signaling adaptor activityGO:0035591

comparative proximal BCR role

PMID:9705962
SLP-65: a new signaling component in B lymphocytes which requires expression of the antigen receptor for phosphorylation.
Native murine B-cell SLP-65/BLNK is a receptor-dependent phosphoprotein in the BCR transducer complex; binding studies and receptor-reconstitution experiments support its adaptor role.
SLP-65 is part of a BCR transducer complex.

The individual mouse review separates native experiments from cross-species biochemical inference. This segment does not assert a complete reviewed mouse p85/adaptor implementation.

Part: Plcg2 comparator
Plcg2 mouse comparatorRegulatory Stepmouse_plcg2_plc_step

The individual mouse review separates native experiments from cross-species biochemical inference. This segment does not assert a complete reviewed mouse p85/adaptor implementation.

Context
Mus musculusNCBITaxon:10090
PMID:12235209
A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation.
Native mouse p110-delta loss impairs BTK/PLCG2 activation and calcium signaling, supporting the PI3K contribution upstream of this branch.
p110delta function is required for BCR-mediated calcium flux, activation of phosphlipaseCgamma2, and Bruton's tyrosine kinase.
PMID:24167721
B lymphocyte antigen receptor signaling: initiation, amplification, and regulation.
BLNK is a phosphotyrosine scaffold connecting kinase activity to effector recruitment. LYN also has inhibitory roles and CD19/BCAP contributions vary with stimulus; a rigid linear kinase chain is insufficient.
Phospho-Blnk serves as a scaffold for the assembly of the other components

Annotons

Plcg2: comparative proximal BCR role
mouse_plcg2_plc
Participant: Gene Product: Plcg2
Gene Product:
Plcg2UniProtKB:Q8CIH5
Family:
Plcg2 classificationPANTHER:PTHR10336:SF25 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: Plcg2UniProtKB:Q8CIH5
Taxon:
Mus musculusNCBITaxon:10090

Function

phosphatidylinositol-4,5-bisphosphate phospholipase C activityGO:0004435

comparative proximal BCR role

PMID:12235209
A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation.
Native mouse p110-delta loss impairs BTK/PLCG2 activation and calcium signaling, supporting the PI3K contribution upstream of this branch.
p110delta function is required for BCR-mediated calcium flux, activation of phosphlipaseCgamma2, and Bruton's tyrosine kinase.
PMID:11043765
Regulation of the phospholipase C-gamma2 pathway in B cells.
The reviewed PLCG2 reaction hydrolyses PIP2 to lipid second messengers; IP3 acts on a separate ER channel. This is pathway/chemistry synthesis across experimental systems, not a new native-species enzyme assay.
The activated PLC-gamma2 converts phosphatidylinositol 4,5-bisphosphate into the second messenger inositol 1,4,5-trisphosphate (IP3), which in turn binds to IP3 receptors located on the endoplasmic reticulum (ER).

The individual mouse review separates native experiments from cross-species biochemical inference. This segment does not assert a complete reviewed mouse p85/adaptor implementation.

Part: Pik3cd comparator
Pik3cd mouse comparatorRegulatory Stepmouse_pik3cd_pi3k_step

The individual mouse review separates native experiments from cross-species biochemical inference. This segment does not assert a complete reviewed mouse p85/adaptor implementation.

Context
Mus musculusNCBITaxon:10090
PMID:12235209
A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation.
Native mouse p110-delta loss impairs BTK/PLCG2 activation and calcium signaling, supporting the PI3K contribution upstream of this branch.
p110delta function is required for BCR-mediated calcium flux, activation of phosphlipaseCgamma2, and Bruton's tyrosine kinase.
PMID:16179367
Key role of the p110delta isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110delta function in B cells.
Acute isoform-selective inhibition reproduces the mouse genetic BCR defect, reducing the risk of assigning a purely developmental consequence as proximal signaling.
a p110delta-selective small molecule inhibitor mirrors the effect of genetic inactivation of p110delta in BCR signaling.
PMID:20699475
The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development.
Mouse alpha/delta compensation concerns tonic signaling; the assayed antigen-triggered response instead depends on delta. Limit isoform specificity to the tested boundary.
Unlike p110delta, however, p110alpha did not contribute to agonist-induced BCR signaling.

Annotons

Pik3cd: comparative proximal BCR role
mouse_pik3cd_pi3k
Participant: Gene Product: Pik3cd
Gene Product:
Pik3cdUniProtKB:O35904
Family:
Pik3cd classificationPANTHER:PTHR10048:SF35 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: Pik3cdUniProtKB:O35904
Taxon:
Mus musculusNCBITaxon:10090

Function

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

comparative proximal BCR role

PMID:12235209
A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation.
Native mouse p110-delta loss impairs BTK/PLCG2 activation and calcium signaling, supporting the PI3K contribution upstream of this branch.
p110delta function is required for BCR-mediated calcium flux, activation of phosphlipaseCgamma2, and Bruton's tyrosine kinase.
PMID:16179367
Key role of the p110delta isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110delta function in B cells.
Acute isoform-selective inhibition reproduces the mouse genetic BCR defect, reducing the risk of assigning a purely developmental consequence as proximal signaling.
a p110delta-selective small molecule inhibitor mirrors the effect of genetic inactivation of p110delta in BCR signaling.
PMID:20699475
The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development.
Mouse alpha/delta compensation concerns tonic signaling; the assayed antigen-triggered response instead depends on delta. Limit isoform specificity to the tested boundary.
Unlike p110delta, however, p110alpha did not contribute to agonist-induced BCR signaling.
PMID:9235916
p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes.
Human leukocyte and mouse embryo p110-delta cloning, recombinant lipid phosphorylation and p85 association establish the class IA enzyme architecture. This abstract reports PI as substrate and is not by itself an exact PIP2-specificity assay.
Recombinant p110delta phosphorylates phosphatidylinositol and coimmunoprecipitates with p85.

The individual mouse review separates native experiments from cross-species biochemical inference. This segment does not assert a complete reviewed mouse p85/adaptor implementation.

Part: avian comparative evidence segment (optional)
Chicken DT40 kinase/scaffold comparatorsSignaling Pathwaychicken_dt40_comparative_segment

Three reviewed chicken products distinguish native knockout mechanisms from heterologous rescue. This is not a complete avian pathway.

Context
Gallus gallusNCBITaxon:9031
PMID:17623905
Genetic analysis of B cell signaling.
DT40 genetics is a major mechanistic evidence source. The chicken knockout host does not establish the species of each rescue construct or a complete native avian circuit.
a chicken DT40 B-cell line
PMID:8137818
Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+ mobilization through distinct pathways.
LYN and SYK loss have different calcium/IP3 effects. LYN is not modeled as the uniquely indispensable kinase for all activated BCR routes.
Lyn-deficient cells evoked a delayed and slow Ca2+ mobilization, despite the normal kinetics of IP3 turnover.
PMID:8691147
A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2.
BTK loss in DT40 reduces PLCG2 phosphorylation and eliminates the measured phosphoinositide/calcium response. BTK and SYK act together; direct substrate chemistry requires more than this knockout.
PLC-gamma 2 activation is regulated by Btk and Syk through their concerted actions.
Part: SYK comparator
SYK chicken comparatorRegulatory Stepchick_syk_kinase_step

Native knockout and rescue-construct evidence are distinguished in the individual review. Human rescue proteins are not counted as native chicken biochemical characterization.

Context
Gallus gallusNCBITaxon:9031
PMID:8137818
Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+ mobilization through distinct pathways.
LYN and SYK loss have different calcium/IP3 effects. LYN is not modeled as the uniquely indispensable kinase for all activated BCR routes.
Lyn-deficient cells evoked a delayed and slow Ca2+ mobilization, despite the normal kinetics of IP3 turnover.
PMID:8691147
A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2.
BTK loss in DT40 reduces PLCG2 phosphorylation and eliminates the measured phosphoinositide/calcium response. BTK and SYK act together; direct substrate chemistry requires more than this knockout.
PLC-gamma 2 activation is regulated by Btk and Syk through their concerted actions.

Annotons

SYK: native DT40 signaling component with construct-specific rescue evidence
chick_syk_kinase
Participant: Gene Product: SYK
Gene Product:
SYKUniProtKB:F1N9Y5
Family:
SYK classificationPANTHER:PTHR24418 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: SYKUniProtKB:F1N9Y5
Taxon:
Gallus gallusNCBITaxon:9031

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

native DT40 signaling component with construct-specific rescue evidence

PMID:8137818
Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+ mobilization through distinct pathways.
LYN and SYK loss have different calcium/IP3 effects. LYN is not modeled as the uniquely indispensable kinase for all activated BCR routes.
Lyn-deficient cells evoked a delayed and slow Ca2+ mobilization, despite the normal kinetics of IP3 turnover.
PMID:8691147
A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2.
BTK loss in DT40 reduces PLCG2 phosphorylation and eliminates the measured phosphoinositide/calcium response. BTK and SYK act together; direct substrate chemistry requires more than this knockout.
PLC-gamma 2 activation is regulated by Btk and Syk through their concerted actions.
PMID:11434777
Bruton's tyrosine kinase is essential for hydrogen peroxide-induced calcium signaling.
DT40 perturbations identify SYK-dependent BLNK tyrosine phosphorylation under oxidative stimulation. This supports the kinase-to-adaptor capability in chicken cells, while antigen-triggered context is supplied by the separate BCR experiments.
hydrogen peroxide stimulates a Syk-, but not Btk-, dependent tyrosine phosphorylation of B cell linker protein BLNK.

Native knockout and rescue-construct evidence are distinguished in the individual review. Human rescue proteins are not counted as native chicken biochemical characterization.

Part: BTK comparator
BTK chicken comparatorRegulatory Stepchick_btk_kinase_step

Native knockout and rescue-construct evidence are distinguished in the individual review. Human rescue proteins are not counted as native chicken biochemical characterization.

Context
Gallus gallusNCBITaxon:9031
PMID:8691147
A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2.
BTK loss in DT40 reduces PLCG2 phosphorylation and eliminates the measured phosphoinositide/calcium response. BTK and SYK act together; direct substrate chemistry requires more than this knockout.
PLC-gamma 2 activation is regulated by Btk and Syk through their concerted actions.

Annotons

BTK: native DT40 signaling component with construct-specific rescue evidence
chick_btk_kinase
Participant: Gene Product: BTK
Gene Product:
BTKUniProtKB:Q8JH64
Family:
BTK classificationPANTHER:PTHR24418 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: BTKUniProtKB:Q8JH64
Taxon:
Gallus gallusNCBITaxon:9031

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

native DT40 signaling component with construct-specific rescue evidence

PMID:8691147
A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2.
BTK loss in DT40 reduces PLCG2 phosphorylation and eliminates the measured phosphoinositide/calcium response. BTK and SYK act together; direct substrate chemistry requires more than this knockout.
PLC-gamma 2 activation is regulated by Btk and Syk through their concerted actions.

Native knockout and rescue-construct evidence are distinguished in the individual review. Human rescue proteins are not counted as native chicken biochemical characterization.

Part: BLNK comparator
BLNK chicken comparatorRegulatory Stepchick_blnk_adaptor_step

Native knockout and rescue-construct evidence are distinguished in the individual review. Human rescue proteins are not counted as native chicken biochemical characterization.

Context
Gallus gallusNCBITaxon:9031
PMID:12456653
BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins.
Multiple human BLNK phosphotyrosines organize different effectors in cis, supporting scaffold activity rather than generic binding or a fixed unverified stoichiometry.
phosphorylation of five tyrosine residues within human BLNK nucleates distinct signaling effectors
PMID:17623905
Genetic analysis of B cell signaling.
DT40 genetics is a major mechanistic evidence source. The chicken knockout host does not establish the species of each rescue construct or a complete native avian circuit.
a chicken DT40 B-cell line

Annotons

BLNK: native DT40 signaling component with construct-specific rescue evidence
chick_blnk_adaptor
Participant: Gene Product: BLNK
Gene Product:
BLNKUniProtKB:Q9YGC1
Family:
BLNK classificationPANTHER:PTHR14098:SF3 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: BLNKUniProtKB:Q9YGC1
Taxon:
Gallus gallusNCBITaxon:9031

Function

signaling adaptor activityGO:0035591

native DT40 signaling component with construct-specific rescue evidence

PMID:12456653
BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins.
Chicken BLNK phosphosite mutants expressed in BLNK-deficient DT40 cells test the scaffold requirement in the native avian ortholog; human and chicken phosphosite numbering are kept distinct.
we expressed the chicken BLNK (cBLNK) ortholog mutant in which the five conserved cBLNK Ys were mutated to F

Native knockout and rescue-construct evidence are distinguished in the individual review. Human rescue proteins are not counted as native chicken biochemical characterization.

Part: PI3K isoform boundary (optional)
Class IB PI3K boundary comparisonRegulatory Stephuman_pi3kgamma_boundary

Developmental, chemokine and cell-extrinsic gamma effects are distinct from the default antigen-triggered p85-associated branch.

Context
Homo sapiensNCBITaxon:9606
PMID:23551098
Rules of engagement: distinct functions for the four class I PI3K catalytic isoforms in immunity.
Class IA p85-associated PI3K and class IB p110-gamma are distinct recruitment architectures. Antigen-dependent delta signaling must be separated from alpha/delta compensation in tonic signaling.
p110γ which is bound by a Gβγ-binding p101 or p84 regulatory subunit is preferentially activated by G-protein coupled receptors.
PMID:20200404
The catalytic PI3K isoforms p110gamma and p110delta contribute to B cell development and maintenance, transformation, and proliferation.
Gamma/delta mouse double deficiency has real developmental and cell-extrinsic effects. Retain the complete PIK3CG gene review without using gamma as the default p85-associated BCR catalytic component.
this was not observed when purified B cells were analyzed

Annotons

PIK3CG: class IB comparison outside the default p85-associated BCR route
human_pik3cg_pi3k
Participant: Gene Product: PIK3CG
Gene Product:
PIK3CGUniProtKB:P48736
Family:
PIK3CG classificationPANTHER:PTHR10048:SF34 Classification of this exact reviewed exemplar. Broad family membership does not make related kinases, adaptors or isoforms interchangeable in this role.
Representative Members: PIK3CGUniProtKB:P48736
Taxon:
Homo sapiensNCBITaxon:9606

Function

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

class IB comparison outside the default p85-associated BCR route

PMID:23551098
Rules of engagement: distinct functions for the four class I PI3K catalytic isoforms in immunity.
Class IA p85-associated PI3K and class IB p110-gamma are distinct recruitment architectures. Antigen-dependent delta signaling must be separated from alpha/delta compensation in tonic signaling.
p110γ which is bound by a Gβγ-binding p101 or p84 regulatory subunit is preferentially activated by G-protein coupled receptors.
PMID:20200404
The catalytic PI3K isoforms p110gamma and p110delta contribute to B cell development and maintenance, transformation, and proliferation.
Gamma/delta mouse double deficiency has real developmental and cell-extrinsic effects. Retain the complete PIK3CG gene review without using gamma as the default p85-associated BCR catalytic component.
this was not observed when purified B cells were analyzed
PMID:7624799
Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase.
Human p110-gamma is activated by heterotrimeric G-protein subunits and does not associate with p85. Its lipid kinase activity belongs to the class IB boundary comparator, not the human p85/p110-delta BCR assembly.
The p110 gamma enzyme was activated in vitro by both the alpha and beta gamma subunits of heterotrimeric guanosine triphosphate (GTP)-binding proteins (G proteins) and did not interact with p85.

Its complete individual review is retained. The gamma isoform does not substitute for the concrete p85-alpha/p110-delta assembly; no BCR-to-gamma causal edge is asserted.