A Novel Transmembrane Protein Recruits Numb to the Plasma Membrane during Asymmetric Cell Division

Numb, an evolutionarily conserved cell fate-determining factor, plays a pivotal role in the development of Drosophila and vertebrate nervous systems. Despite lacking a transmembrane segment, Numb is associated with the cell membrane during the asymmetric cell division of Drosophila neural precursor cells and is selectively partitioned to one of the two progeny cells from a binary cell division. Numb contains an N-terminal phosphotyrosine-binding (PTB) domain that is essential for both the asymmetric localization and the fate specification function of Numb. We report here the isolation and characterization of a novel PTB domain-binding protein, NIP (Numb-interacting protein). NIP is a multipass transmembrane protein that contains two PTB domain-binding, NXXF motifs required for the interaction with Numb. In dividing Drosophila neuroblasts, NIP is colocalized to the cell membrane with Numb in a basal cortical crescent. Expression of NIP in Cos-7 cells recruited Numb from the cytosol to the plasma membrane. This recruitment of Numb to membrane by NIP was dependent on the presence of at least one NXXF site. In Drosophila Schneider 2 cells, NIP and Numb were colocalized at the plasma membrane. Inhibition of NIP expression by RNA interference released Numb to the cytosol. These results suggest that a direct protein-protein interaction between NIP and Numb is necessary and sufficient for the recruitment of Numb to the plasma membrane. Recruitment of Numb to a basal cortical crescent in a dividing neuroblast is essential for Numb to function as an intrinsic cell fate determinant. Numb, an evolutionarily conserved cell fate-determining factor, plays a pivotal role in the development of Drosophila and vertebrate nervous systems. Despite lacking a transmembrane segment, Numb is associated with the cell membrane during the asymmetric cell division of Drosophila neural precursor cells and is selectively partitioned to one of the two progeny cells from a binary cell division. Numb contains an N-terminal phosphotyrosine-binding (PTB) domain that is essential for both the asymmetric localization and the fate specification function of Numb. We report here the isolation and characterization of a novel PTB domain-binding protein, NIP (Numb-interacting protein). NIP is a multipass transmembrane protein that contains two PTB domain-binding, NXXF motifs required for the interaction with Numb. In dividing Drosophila neuroblasts, NIP is colocalized to the cell membrane with Numb in a basal cortical crescent. Expression of NIP in Cos-7 cells recruited Numb from the cytosol to the plasma membrane. This recruitment of Numb to membrane by NIP was dependent on the presence of at least one NXXF site. In Drosophila Schneider 2 cells, NIP and Numb were colocalized at the plasma membrane. Inhibition of NIP expression by RNA interference released Numb to the cytosol. These results suggest that a direct protein-protein interaction between NIP and Numb is necessary and sufficient for the recruitment of Numb to the plasma membrane. Recruitment of Numb to a basal cortical crescent in a dividing neuroblast is essential for Numb to function as an intrinsic cell fate determinant. Asymmetric cell division, which can involve extrinsic and/or intrinsic factors, is a fundamental mechanism of generating cell diversity during the development of complex organisms (1Horvitz H.R. Herskowitz I. Cell. 1992; 68: 237-458Abstract Full Text PDF PubMed Scopus (430) Google Scholar, 2Jan Y.N. Jan L.Y. Nature. 1998; 392: 775-778Crossref PubMed Scopus (236) Google Scholar). Extrinsic factors such as Delta and its receptor Notch (3Kidd S. Kelley M.R. Young M.W. Mol. Cell. Biol. 1986; 6: 3094-3108Crossref PubMed Scopus (292) Google Scholar, 4Weinmaster G. Roberts V.J. Lemke G. Development. 1991; 113: 199-280Crossref PubMed Google Scholar) function in cell-cell communication to specify the fate of cells (5Fortini M.E. Rebay I. Caron L.A. Artavanis-Tsakonas S Nature. 1993; 365: 555-557Crossref PubMed Scopus (258) Google Scholar, 6Artavanis-Tsakonas M.D., S.R. Lake R.J. Science. 1999; 284: 770-776Crossref PubMed Scopus (4820) Google Scholar, 7Wakamatsu Y. Maynard T.M. Weston J.A. Development. 2000; 127: 2811-2821Crossref PubMed Google Scholar). Asymmetric determinants are intrinsic factors that are selectively segregated into one of the two daughter cells when a cell divides (2Jan Y.N. Jan L.Y. Nature. 1998; 392: 775-778Crossref PubMed Scopus (236) Google Scholar, 8Lu B. Jan L.Y. Jan Y.N. Curr. Opin. Genet. Dev. 1998; 8: 392-399Crossref PubMed Scopus (46) Google Scholar). Consequently, the sibling cell that inherits the asymmetric determinants adopts a different fate from the one that does not. Numb is a member of a growing family of proteins that also includes Prospero, Miranda, Inscuteable, and PON (partner of numb) (9Uemura T. Shepherd S. Ackerman L. Jan L.Y. Jan Y.N. Cell. 1989; 58: 349-360Abstract Full Text PDF PubMed Scopus (405) Google Scholar, 10Hirata J. Nakagoshi H. Nabeshima Y. Matsuzaki F. Nature. 1995; 377: 627-630Crossref PubMed Scopus (297) Google Scholar, 11Shen C.P. Jan L.Y. Jan Y.N. Cell. 1997; 90: 449-458Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 12Ikeshima-Kataoka H. Skeath J.B. Nabeshima Y. Doe C.Q. Matsuzaki F. Nature. 1997; 390: 625-629Crossref PubMed Scopus (254) Google Scholar, 13Kraut R. Chia W. Jan L.Y. Jan Y.N. Knoblich J.A. Nature. 1996; 383: 50-55Crossref PubMed Scopus (320) Google Scholar, 14Lu B. Rothenberg M. Jan L.Y. Jan Y.N. Cell. 1998; 95: 225-235Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar), which act as intrinsic determinants in asymmetric cell division. These proteins were identified through their requirement in the development of Drosophila peripheral and central nervous systems. The external sensory organ in Drosophila is composed of two outer (hair and socket) cells and three inner (sheath, glial, and neuron) cells, which are derived from a single sensory organ precursor through three consecutive asymmetric cell divisions. Numb is selectively partitioned to one of the two daughter cells at each binary division (15Jan Y.N. Jan L.Y. Nat. Rev. Neurosci. 2001; 2: 772-779Crossref PubMed Scopus (120) Google Scholar). Numb is also required for the development of the central nervous system (16Spana E.P. Kopczynski C. Goodman C.S. Doe C.Q. Development. 1995; 121: 3489-3494Crossref PubMed Google Scholar, 17Spana E.P. Doe C.Q. Neuron. 1996; 17: 21-26Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar, 18Knoblich J.A. Nat. Rev. Mol. Cell. Biol. 2001; 2: 11-20Crossref PubMed Scopus (241) Google Scholar). During delaminating from the neuroectoderm and asymmetric division of a neuroblast, Numb, Prospero, and several other proteins are co-localized in a basal cortical crescent. These proteins are partitioned to the basal daughter cell or the ganglion mother cell, which will divide once more, generating two neurons or a neuron and a glial cell. The apical daughter to which the proteins were not partitioned maintains the neuroblast characteristics and is capable of undergoing several additional rounds of cell division (18Knoblich J.A. Nat. Rev. Mol. Cell. Biol. 2001; 2: 11-20Crossref PubMed Scopus (241) Google Scholar). The amino acid sequence of Numb suggests that it may function as an adaptor protein capable of mediating protein-protein interactions (19Pawson T. Scott J.D. Science. 1997; 278: 2075-2080Crossref PubMed Scopus (1883) Google Scholar). The N-terminal portion of Numb contains a phosphotyrosine-binding (PTB) 1The abbreviations used are: PTB, phosphotyrosine-binding; GST, glutathione S-transferase; FITC, fluorescein isothiocyanate; HEK, human embryonic kidney; ds, double-stranded; TM, transmembrane; IP, immunoprecipitation; aPKC, atypical protein kinase C. 1The abbreviations used are: PTB, phosphotyrosine-binding; GST, glutathione S-transferase; FITC, fluorescein isothiocyanate; HEK, human embryonic kidney; ds, double-stranded; TM, transmembrane; IP, immunoprecipitation; aPKC, atypical protein kinase C. domain, a protein-protein interaction module important in receptor tyrosine kinase signaling (20Kavanaugh W.M. Williams L.T. Science. 1994; 266: 1862-1865Crossref PubMed Scopus (447) Google Scholar, 21Blaikie P. Immanuel D. Wu J. Li N. Yajnik V. Margolis B. J. Biol. Chem. 1994; 269: 32031-432034Abstract Full Text PDF PubMed Google Scholar). The C-terminal part of the protein contains a proline-rich region that can potentially interact with proteins containing the SH3 domain (22Ren R. Mayer B.J. Cicchetti P. Baltimore D. Science. 1993; 259: 1157-1161Crossref PubMed Scopus (1015) Google Scholar). Genetic and biochemical evidence from Drosophila suggest that Numb may interact with Notch to antagonize its function such that the Notch-mediated cell-cell interaction is asymmetric (17Spana E.P. Doe C.Q. Neuron. 1996; 17: 21-26Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar, 23Frise E. Knoblich J.A. Younger-Shepherd S. Jan L.Y. Jan Y.N. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 11925-11932Crossref PubMed Scopus (259) Google Scholar). Similarly, the mammalian Numb homologue, mNumb, physically interacts with mouse Notch1 (24Zhong W. Feder J.N. Jiang Jan L.Y. Jan Y.N. Neuron. 1996; 17: Full Text Full Text PDF PubMed Scopus Google Scholar) and Notch1 by its and J. Biol. Chem. 278: Full Text Full Text PDF PubMed Scopus Google Scholar). In to Numb interacts through its PTB domain with and of Numb B. Rothenberg M. Jan L.Y. Jan Y.N. Cell. 1998; 95: 225-235Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, S. Rothenberg M. Jan L.Y. Jan Y.N. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar, S. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). PON is an adaptor protein required for the basal localization of Numb during the asymmetric division of a neuroblast the B. Rothenberg M. Jan L.Y. Jan Y.N. Cell. 1998; 95: 225-235Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar). is to a kinase that Numb function S. Rothenberg M. Jan L.Y. Jan Y.N. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar). is a protein containing a and that as an for the and of J. M. J. PubMed Scopus Google Scholar). The of of for Numb the of its PTB the of PTB that tyrosine for the Numb PTB domain is capable of of which are of C. S. L. J. T. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, C. T. J.D. Nat. Biol. 1998; PubMed Scopus Google Scholar, C. Li T. J.D. J. 2000; PubMed Scopus Google Scholar). the Numb PTB domain-binding in contains an S. Rothenberg M. Jan L.Y. Jan Y.N. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar), the conserved PTB domain to an sequence in S. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. J. PubMed Scopus Google Scholar). of the mechanism of Numb function as an intrinsic cell fate with the of a fundamental is the protein Numb recruited to the cell membrane in a crescent a neuroblast, which is a for the of Numb into one of two daughter cells at cell Numb a transmembrane segment, its recruitment to the membrane involve one of several by to a membrane by or with a membrane protein, or by a protein J.A. Jan L.Y. Jan Y.N. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar, J.A. Jan Jan Y.N. Nature. 1995; 377: PubMed Scopus Google Scholar). Asymmetric localization of Numb in the PTB domain J.A. Jan L.Y. Jan Y.N. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). The pivotal role of the PTB domain is by the that it is not for Numb localization during sensory organ precursor and neuroblast division also for the specification of sibling cell J.A. Jan L.Y. Jan Y.N. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, M. Jan L. Jan Y.N. Neuron. 1996; 17: Full Text Full Text PDF PubMed Scopus Google Scholar, L. J. M. C. R. Margolis B. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the Numb PTB domain suggests that additional proteins may that Numb to the plasma membrane. for a Drosophila embryonic an Numb PTB domain as a and identified a protein that NIP (Numb-interacting protein). NIP is an intrinsic membrane protein that interacts with Numb in and in and is required for the membrane recruitment of Numb. to Drosophila NIP were identified in other from to that the function of NIP is evolutionarily Expression and of Drosophila Numb PTB domain was from as C. Li T. J.D. J. 2000; PubMed Scopus Google Scholar). PTB domain was with the and used to a Drosophila embryonic with the the to were identified by a as The were for in the a of were of which with one and were derived from a single The from a of a This sequence was used to the Drosophila expression sequence and several expression sequence were The expression sequence an that a protein of amino and the sequence was and into a and NIP was by into or as of and were by and into Drosophila Numb amino was into a or a Numb and of Numb, and were into a and as in E. Drosophila Numb was a containing the C-terminal of Numb. was a derived from the of the were and with or and were from was from was from and was from mouse was from and in RNA from the or of Drosophila was the H. T. G. J. 2001; PubMed Scopus Google Scholar). of of RNA was by on a and to a membrane The was and at to RNA to of the NIP with RNA for the NIP and Numb were by in with or RNA with to The were in and to the at the to for 2 a was by with and embryonic and Cos-7 cells were at in containing and the cells were to to in and of was with in and were as C. Li J. Biol. Chem. 278: Full Text Full Text PDF PubMed Scopus Google Scholar). and containing the or the were on an was to the of the in the presence of The was the acid and with a were as C. Li J. Biol. Chem. 278: Full Text Full Text PDF PubMed Scopus Google Scholar). the localization of NIP in were from to at in and in in The were for for at and to the for 2 This is by a with at in for at The of cells were with were on a a direct interaction between NIP and Numb in cells, Cos-7 cells were with Numb in the presence or of or a and were used to NIP in The was used for The were cells were in Drosophila with at The was to N. M. T. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). NIP RNA was by in with or RNA the cells were to a of in Drosophila expression system and in with RNA was to the of at 2 of Drosophila with was and for the cells were and by at The cell were in of and of was used on a were as and were used at was at of a Drosophila a Numb PTB domain was used to a Drosophila embryonic of the of the 2000; PubMed Scopus Google Scholar). The expression sequence was used to the which a protein of amino with a of The protein was The NIP to the region on in the Drosophila 2000; PubMed Scopus Google Scholar). by J. T. C.P. P. 2000; PubMed Scopus Google Scholar, I. L. T. J. R. F. C.P. P. PubMed Scopus Google Scholar) suggest that NIP is a membrane protein with transmembrane at a with of the other is NIP an of a receptor Sci. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In two Numb PTB domain-binding and were between and and at the C-terminal portion of the protein, 1The a membrane sequence of the and the protein J. R. J. Mol. Biol. PubMed Scopus Google Scholar) is by The two PTB domain-binding, NXXF motifs are identified in of Drosophila NIP with from other identified sequence are or to or conserved in NIP proteins is identified by a sequence protein several proteins in from to that sequence with Drosophila sequence was at the N-terminal of the proteins that the transmembrane the C-terminal were conserved the two Numb PTB domain-binding the by a sequence of an amino is conserved in the by the sequence was by the and Drosophila NIP proteins two mouse NIP were of which one sequence to the or human mammalian for are at the to Drosophila of NIP in Drosophila and the NIP in of NIP was by RNA was from Drosophila and and to NIP in a of was in and The of the to the of the The NIP was in and and was in This of NIP the at the is of that of Numb (9Uemura T. Shepherd S. Ackerman L. Jan L.Y. Jan Y.N. Cell. 1989; 58: 349-360Abstract Full Text PDF PubMed Scopus (405) Google Scholar). to the NIP protein were a to the C-terminal of the protein of Drosophila embryonic a at which with the of of a in and in were to Numb and NIP can interact with each other in on glutathione was used to Numb from of cells with Numb in was capable of Numb from cell the to In a was to NIP from cells These results that NIP and Numb interact with each other in that interaction in used the Drosophila in a of the of NIP and it to was cells were with for Numb and and the cell was to a mouse a or in Numb was in not in NIP was to with Numb These that a interaction can in the of a cell. PTB the of Numb with NIP was as a PTB domain-binding protein, it is necessary to other in Numb to the three to the the PTB domain and the C-terminal region of Numb were and into a The Numb as were used to NIP from was to NIP from cells, the other two of Numb and the to the in NIP for Numb a of were that or both of the for the Numb PTB domain These NIP were in cells, one at a in with Numb. were to their to Numb. and which one or both of the NXXF were capable of Numb. In the and C-terminal and which the PTB domain-binding not is from that the PTB domain in Numb and the two NXXF motifs in NIP are essential for the protein-protein a direct of the NXXF motifs in Numb two derived from the and the were and with The of Numb PTB domain for each of was by in and both the and to the to the Numb PTB domain with of and for the These in the as for other Numb PTB C. Li T. J.D. J. 2000; PubMed Scopus Google Scholar). The and motifs are to the for Numb in S. Rothenberg M. Jan L.Y. Jan Y.N. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar). The and in the were to essential for the interaction C. Li T. J.D. J. 2000; PubMed Scopus Google Scholar). the in the sequence an important role in Numb PTB domain on the of R. J. PubMed Scopus Google Scholar). of for to Numb PTB domain that in are for each of by an the of the by an in a in PTB domain with the and a of to the of in the NXXF motifs of the NIP protein, two NIP single which at the or the and a both of the was with Numb in cells, and their interaction was by single and for Numb In the the These results suggest that the two NXXF motifs in NIP a direct interaction with Numb. the role of two motifs may the presence of a single is sufficient for Numb PTB domain of NIP and Numb during of that Numb is an essential protein for asymmetric cell division in the Drosophila nervous system development and that NIP interacts with Numb, it is that NIP may a part in asymmetric cell division. at were with a to NIP localization in dividing and with to the NIP was to a crescent at the basal of a neuroblast at which was through to NIP was in the basal daughter cell mother a crescent is on the basal membrane of the apical daughter cell it the ganglion mother cell The of the was in a the This of asymmetric localization for NIP during the division of a neuroblast is to that of Numb at J.A. Jan Jan Y.N. Nature. 1995; 377: PubMed Scopus Google Scholar). two proteins are were with and in NIP and Numb in during the two proteins were to not in at also in the two daughter cells at These results that NIP and Numb may during the asymmetric division of Drosophila NIP and for the Recruitment of Numb from the to the NIP is a membrane protein that interacts and with Numb in and in were in NIP can Numb to the plasma membrane. We NIP and Numb or in in Cos-7 NIP was in the plasma membrane as The Numb protein, on the other in the cytosol when in Cos-7 cells of NIP with Numb in the cells, recruited Numb to the plasma membrane The recruitment of Numb was through a direct interaction of the two This was the of the protein to the plasma membrane it to Numb to the membrane when were in the cell This that the membrane recruitment of Numb was dependent on the NXXF of NIP is necessary for the membrane of Numb in Drosophila cells, used an RNA interference to the of NIP expression on Numb We the localization of NIP and Numb in NIP and Numb to the plasma membrane of cells of cells with RNA in of NIP expression in a of cells In the cells that NIP Numb was in the it on the membrane in the cell that NIP and a of was the cells The NIP of Numb to the cytosol is also in a cell was with and The of NIP was also in in expression of NIP was by in cells, the of Numb is the in both and that NIP is necessary for the membrane of Numb in NIP a for central in asymmetric cell division is intrinsic cell fate determinants are during Numb, Prospero, and proteins a basal cortical crescent at when a neuroblast divides the and from the (18Knoblich J.A. Nat. Rev. Mol. Cell. Biol. 2001; 2: 11-20Crossref PubMed Scopus (241) Google Scholar, M. Knoblich J.A. 2001; PubMed Scopus Google Scholar). Asymmetric localization of determinants is to in two the to the plasma membrane and the of cortical M. Knoblich J.A. 2001; PubMed Scopus Google Scholar). Numb does not a transmembrane or a and its recruitment to the plasma membrane may by a and/or a protein of the membrane. The N-terminal region of Numb, the PTB domain, was to necessary for the membrane recruitment and asymmetric localization of Numb J.A. Jan L.Y. Jan Y.N. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). the PTB domain was identified as a protein module that interacts with of the such as the and PTB are also capable of to M. Nature. 1995; PubMed Scopus Google Scholar, R. J.A. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar) and are in membrane the Numb PTB domain does not to The of the Numb PTB domain-binding protein NIP a mechanism for the membrane localization of Numb. NIP is to a membrane protein with and is to the plasma membrane in Cos-7 cells and in Drosophila Numb can recruited to and on the plasma membrane a direct protein-protein interaction with a direct protein-protein interaction is by the Numb PTB domain and the two NXXF of In Drosophila neuroblasts, NIP with Numb in basal cortical In Drosophila embryonic cells, the membrane of Numb is dependent on of NIP protein in Numb to the cytosol. NIP both necessary and sufficient for the recruitment and of Numb in the plasma membrane. a of the PTB domain was to the neuroblast membrane when in Drosophila J.A. Jan L.Y. Jan Y.N. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). does not interact with NIP in it is that it may interact with NIP or that other of Numb membrane localization NIP and Asymmetric of NIP a role in the of basal Numb in additional such as the of NIP is to a to it is to that NIP may a part in the asymmetric of Numb. of evidence NIP is in delaminating and a basal cortical crescent at the NIP crescent and the Numb crescent from through of a cell is that the of a NIP crescent the of the Numb crescent by a direct protein-protein is the NIP crescent in a The mechanism that the localization of other basal determinants may also direct the localization of NIP (2Jan Y.N. Jan L.Y. Nature. 1998; 392: 775-778Crossref PubMed Scopus (236) Google Scholar). is essential for asymmetric Numb localization to the basal in R. Chia W. Jan L.Y. Jan Y.N. Knoblich J.A. Nature. 1996; 383: 50-55Crossref PubMed Scopus (320) Google Scholar, F. Y. Chia W. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is to the apical an that is dependent on the Drosophila of M. M. Knoblich J.A. Nature. 1999; PubMed Scopus Google Scholar). In Drosophila and cells, to the apical membrane and a complex with the Drosophila and the atypical protein kinase homologue, M. Knoblich J.A. Nat. Biol. 2001; PubMed Scopus Google Scholar, A. A. A. E. J. Biol. 2000; PubMed Scopus Google Scholar). not an apical for the localization of M. M. Knoblich J.A. Nature. 1999; PubMed Scopus Google with and it also the localization of basal determinants such as Numb, Miranda, and M. Knoblich J.A. Nat. Biol. 2001; PubMed Scopus Google Scholar, A. A. A. E. J. Biol. 2000; PubMed Scopus Google Scholar). In mammalian cells, an complex is and D. G. Scott J.D. T. Nat. Biol. 2000; 2: PubMed Scopus Google Scholar, S. A. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, L. Margolis B. Nat. Biol. PubMed Scopus Google Scholar). it is not the apical complex of is to the apical a mechanism is through interactions with membrane proteins such as an membrane protein capable of to through its domain and to the plasma membrane L. Margolis B. Nat. Biol. PubMed Scopus Google Scholar). is that NIP may the basal protein complex of Numb, and through to the Numb PTB domain in a to the role of in the membrane recruitment of and the apical does an apical complex direct basal of The between the of cell and asymmetric localization of determinants was in the was identified as a of J. Knoblich J.A. Nature. PubMed Scopus Google Scholar, S. T. Nat. Biol. PubMed Scopus Google Scholar), and of by the results in its and from the apical crescent J. Knoblich J.A. Nature. PubMed Scopus Google Scholar, T. Y. Y. C. A. T. A. A. S. Curr. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). at the basal crescent to essential for the basal of and PON J. Knoblich J.A. Nature. PubMed Scopus Google Scholar). to basal localization of NIP in a neuroblast is by a for of NIP in asymmetric cell division is in the presence of proteins with a of amino acid in other one of the two Numb PTB identified in Drosophila NIP is conserved in mammalian NIP that the conserved was sufficient for mediating a interaction between NIP and the Numb PTB This is also capable of mediating an interaction between mammalian Numb and human NIP not is that mammalian NIP proteins a role in localization and We for

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