Interaction of TAPP adapter proteins with phosphatidylinositol (3,4)‐bisphosphate regulates B‐cell activation and autoantibody production

Abstract

TAPP1 and TAPP2 (where TAPP is tandem PH domain containing protein) are dual PH domain adaptors that selectively bind PI(3,4)P2 (phosphatidylinositol (3,4)-bisphosphate). PI(3,4)P2 is a lipid messenger generated by phosphoinositide 3-kinase (PI3K)and IntroductionThe phosphoinositide 3-kinase (PI3K) signaling pathway is linked to a number of key cellular processes including lymphocyte cell survival, proliferation, differentiation, and motility [1][2][3].Correspondence: Dr. Aaron J. Marshall e-mail: marshall@ms.umanitoba.ca PI3K functions by phosphorylating the D3 position of membrane phosphoinositides (PIs) generating PI(3)P, PI(3,4)P2, and PI(3,4,5)P3. These D3 PIs regulate various cellular processes through the recruitment of effector proteins containing PI-binding domains [4][5][6]. Regulation of this pathway in immune cells is crucial for prevention of leukocyte-derived cancers as well as development of autoimmune diseases [7][8][9][10].The B-cell antigen receptor (BCR) activates PI3K [11] and this pathway plays critical roles in B lymphocyte development and function [12,13]. The PI3K pathway is critical for C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 2760-2770 Leukocyte signaling 2761"tonic" signaling through the BCR, which is required to maintain the survival of mature B cells [14]. PI phosphatases such as PTEN and SHIP function to restrain PI3K signaling by limiting the amount of PI(3,4,5)P3 available for binding [15,16]. In B cells, inhibitory signaling via the receptor FcγRIIB requires binding of SHIP to an ITIM motif in its cytoplasmic tail [17]. SHIP-deficient mice show elevated immunoglobulin levels and increased B-cell proliferation upon BCR-FcγRIIB cross-linking, indicating that SHIP functions as a negative regulator in B cells [18]. PI second messengers regulate various cellular activities by functioning as membrane docking sites for proteins containing PIbinding modules such as PH, PX, or FYVE domains [19]. While PI(3,4,5)P3 is clearly implicated in activation of signaling pathways, the signaling events downstream of PI(3,4)P2 are not well understood. A key PI-dependant protein kinase Akt/PKB can bind both PI(3,4,5)P3 and PI(3,4)P2, and the latter lipid has been suggested to contribute to Akt activation [20,21]; however the direct versus indirect effects of PI(3,4)P2 on Akt activity remains controversial. SHIP, which hydrolyzes PIP3 to generate PI(3,4)P2, has been found in several systems to inhibit Akt activation [18,22], suggesting that PIP3 levels may often be the limiting factor regulating Akt activity.A few proteins are known to selectively bind to PI(3,4)P2, but not PIP3, including PX domain proteins involved in NADPH oxidase regulation [23] and TAPP1 and TAPP2 (where TAPP is tandem PH domain containing proteins) [24]. We previously found that TAPP adapters are expressed in B cells and are recruited to the plasma membrane in response to BCR cross-linking, in a delayed and sustained manner correlating with PI(3,4)P2 levels [25]. TAPP2 membra...

Autoimmunity risk alleles: hotspots in B cell regulatory signaling pathways

“…Furthermore, PtdIns3,4P2 generated by SHIP-1 recruits the inhibitory adaptor proteins TAPP1 and TAPP2. Mice with B celltargeted knockout of SHP-1 (21) or SHIP-1 (22) as well as knockins of inactive TAPPs develop severe lupus-like disease (23). Lyn may also mediate inhibitory signaling via activation of cytosolic mediators such as casein kinase 2, which by phosphorylation of the tail of phosphatase and tensin homolog (PTEN) extends its half-life, promoting its inhibitory functions (24).…”

Phosphatidylinositol (3,4) bisphosphate-specific phosphatases and effector proteins: A distinct branch of PI3K signaling

“…These TAPP KI mice are viable, but show increased whole body insulin sensitivity and glucose uptake into muscle tissues, associated with enhanced insulin-induced Akt activity [74]. Similarly, "over-activation" phenotypes are seen in B cell development and function [73]. …”

“…The physiological role of TAPP proteins through transducing the PI(3,4)P2 signal has been studied using a knock-in mutant mouse strain, TAPP R211L/R211L TAPP2 R218L/R218L (TAPP KI) [73,74]. Introduction of mutations in the PI(3,4)P2-binding pocket of the C-terminal domains of TAPP proteins abolished their ability to bind PI(3,4)P2 without affecting their normal expression levels [74].…”

“…Together, these data suggest an emerging role of the TAPP proteins in negatively regulating cellular metabolic activation via Akt, besides the positive function of TAPP2 in malignant B cell adhesion and migration[61]. One model of negative signaling through PI(3,4)P2-TAPP coupling is that TAPPs recruit inhibitory signaling molecules such as the phosphatase PTPL1 to sites of PI(3,4)P2 accumulation, inhibiting Akt activation[59,73]. An alternative mechanism might be that TAPP-PI(3,4)P2 interaction restricts the availability of PI(3,4)P2 for activation of other PI(3,4)P2-binding proteins such as Akt.…”

B cell expression of the SH2-containing inositol 5-phosphatase (SHIP-1) is required to establish anergy to high affinity, proteinacious autoantigens

“…PTEN attacks its substrate PI(3,4,5)P 3 at the 3 position of the inositol ring, generating the PI(4,5)P 2 substrate of phospholipase C important in positive signaling. SHIP-1 attacks the 5 position of the inositol ring generating PI(3,4)P 2 , a feedback activator of SHIP-1 and stimulator of pathways involving the adaptors TAPP1 and TAPP2 that are thought to inhibit Akt [15]. SHIP-1 also associates with the rasGAP adaptor Dok-1[16].…”