Signaling Pathways Activated by B-Cell Receptor in CLL
BCR consists of an antigen-binding transmembrane immunoglobulin (mIg) in complex with two trans-membrane polypeptides, namely Igα and Igβ, containing immunoreceptor tyrosine activation motifs (ITAMs), which enable the transmission of intracellular signaling. Oligomeric or multimeric antigen engagement leads to BCR cross-linking and phosphorylation of ITAM motifs by the SRC family kinase LYN. The phosphorylated ITAMs recruit the spleen tyrosine kinase (SYK) to the receptor, where it becomes activated by phosphorylation of tyrosines in its kinase domain, and propagates the signal activation to downstream signaling proteins. Activation of SYK is a critical event in BCR signaling, initiating the formation of a plasma membrane-associated signaling complex, named signalosome, which assembles signaling molecules, such as the SYK itself, phospholipase-Cγ2 (PLCγ2), PI3K, Bruton's tyrosine kinase (BTK), VAV1 and adaptor molecules, such as B-cell linker (BLNK). The signalosome coordinates and regulates downstream cellular events, including signaling mediated by second messengers such as increased Ca concentration and the induction of gene expression. During BCR signaling, PLCγ2 and PI3K are crucial signaling intermediates that generate key second messengers, which in turn, activate IKK and ERK (Figure 1). The balance between these signaling events regulates several B-cell fate decisions, including proliferation, survival, differentiation and cell death.
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Figure 1.
B-cell receptor-activation pathways following antigenic stimulation. BCR: B-cell receptor; BLNK: B-cell linker protein; BTK: Bruton's tyrosine kinase; DAG: Diacylglycerol; GSK: Glycogen synthase kinase; IP3: Inositol-1,4,5-trisphosphate; NFAT: Nuclear factor of activated T cells; PIP3: Phosphatidylinositol-3,4,5-triphosphate; PLCγ2: Phospholipase-Cγ2; SYK: Spleen tyrosine kinase.
BCR Signaling Pathways
BCR consists of an antigen-binding transmembrane immunoglobulin (mIg) in complex with two trans-membrane polypeptides, namely Igα and Igβ, containing immunoreceptor tyrosine activation motifs (ITAMs), which enable the transmission of intracellular signaling. Oligomeric or multimeric antigen engagement leads to BCR cross-linking and phosphorylation of ITAM motifs by the SRC family kinase LYN. The phosphorylated ITAMs recruit the spleen tyrosine kinase (SYK) to the receptor, where it becomes activated by phosphorylation of tyrosines in its kinase domain, and propagates the signal activation to downstream signaling proteins. Activation of SYK is a critical event in BCR signaling, initiating the formation of a plasma membrane-associated signaling complex, named signalosome, which assembles signaling molecules, such as the SYK itself, phospholipase-Cγ2 (PLCγ2), PI3K, Bruton's tyrosine kinase (BTK), VAV1 and adaptor molecules, such as B-cell linker (BLNK). The signalosome coordinates and regulates downstream cellular events, including signaling mediated by second messengers such as increased Ca concentration and the induction of gene expression. During BCR signaling, PLCγ2 and PI3K are crucial signaling intermediates that generate key second messengers, which in turn, activate IKK and ERK (Figure 1). The balance between these signaling events regulates several B-cell fate decisions, including proliferation, survival, differentiation and cell death.
(Enlarge Image)
Figure 1.
B-cell receptor-activation pathways following antigenic stimulation. BCR: B-cell receptor; BLNK: B-cell linker protein; BTK: Bruton's tyrosine kinase; DAG: Diacylglycerol; GSK: Glycogen synthase kinase; IP3: Inositol-1,4,5-trisphosphate; NFAT: Nuclear factor of activated T cells; PIP3: Phosphatidylinositol-3,4,5-triphosphate; PLCγ2: Phospholipase-Cγ2; SYK: Spleen tyrosine kinase.
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