Decision letter: Specific Eph receptor-cytoplasmic effector signaling mediated by SAM–SAM domain interactions

AbstractThe Eph receptor tyrosine kinase (RTK) family is the largest subfamily of RTKs playing critical roles in many developmental processes such as tissue patterning, neurogenesis and neuronal circuit formation, angiogenesis, etc. How the 14 Eph proteins, via their highly similar cytoplasmic domains, can transmit diverse and sometimes opposite cellular signals upon engaging ephrins is a major unresolved question. Here we systematically investigated the bindings of each SAM domain of Eph receptors to the SAM domains from SHIP2 and Odin, and uncover a highly specific SAM-SAM interaction-mediated cytoplasmic Eph-effector binding pattern. Comparative X-ray crystallographic studies of several SAM-SAM heterodimer complexes, together with biochemical and cell biology experiments, not only revealed the exquisite specificity code governing Eph/effector interactions but also allowed us to identify SAMD5 as a new Eph binding partner. Finally, these Eph/effector SAM heterodimer structures can explain numerous Eph SAM mutations identified in patients suffering from cancers and other diseases.

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Author response: Specific Eph receptor-cytoplasmic effector signaling mediated by SAM–SAM domain interactions

10.7554/elife.35677.030 ◽

2018 ◽

Author(s):

Yue Wang ◽

Yuan Shang ◽

Jianchao Li ◽

Weidi Chen ◽

Gang Li ◽

...

Keyword(s):

Author Response ◽

Eph Receptor ◽

Sam Domain ◽

Domain Interactions

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Specific Eph receptor-cytoplasmic effector signaling mediated by SAM–SAM domain interactions

eLife ◽

10.7554/elife.35677 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 10

Author(s):

Yue Wang ◽

Yuan Shang ◽

Jianchao Li ◽

Weidi Chen ◽

Gang Li ◽

...

Keyword(s):

Cell Biology ◽

Eph Receptors ◽

Eph Receptor ◽

X Ray ◽

Binding Partner ◽

Sam Domain ◽

Domain Interactions ◽

Circuit Formation ◽

Exquisite Specificity ◽

Effector Binding

The Eph receptor tyrosine kinase (RTK) family is the largest subfamily of RTKs playing critical roles in many developmental processes such as tissue patterning, neurogenesis and neuronal circuit formation, angiogenesis, etc. How the 14 Eph proteins, via their highly similar cytoplasmic domains, can transmit diverse and sometimes opposite cellular signals upon engaging ephrins is a major unresolved question. Here, we systematically investigated the bindings of each SAM domain of Eph receptors to the SAM domains from SHIP2 and Odin, and uncover a highly specific SAM–SAM interaction-mediated cytoplasmic Eph-effector binding pattern. Comparative X-ray crystallographic studies of several SAM–SAM heterodimer complexes, together with biochemical and cell biology experiments, not only revealed the exquisite specificity code governing Eph/effector interactions but also allowed us to identify SAMD5 as a new Eph binding partner. Finally, these Eph/effector SAM heterodimer structures can explain many Eph SAM mutations identified in patients suffering from cancers and other diseases.

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Role of SHIP2 in cell repulsion regulated by Eph receptor and ephrin signaling

10.1101/872846 ◽

2019 ◽

Author(s):

Tim G. Ashlin ◽

Zhonglin Wu ◽

Qiling Xu ◽

David G. Wilkinson

Keyword(s):

Sh2 Domain ◽

Distinct Mode ◽

Eph Receptor ◽

Sam Domain ◽

Cell Responses ◽

Phosphoinositide Phosphatase ◽

Cell Segregation ◽

Cell Repulsion

SUMMARYPrevious studies have found that activation of EphB2 and ephrinB1 that drives cell segregation leads to phosphorylation of the phosphoinositide phosphatase SHIP2 downstream of forward (EphB2) but not reverse (ephrinB1) signaling. We have analysed whether SHIP2 interacts with EphB2 and contributes to cell responses to EphB2-ephrinB1 signaling. We confirm that EphB2 activation leads to SHIP2 phosphorylation on Y1135 and find that they interact through the SH2 domain of SHIP2. There is thus a distinct mode of interaction from EphA2, which binds SHIP2 via its SAM domain. Knockdown of SHIP2 in EphB2 cells leads to decreased segregation from ephrinB1 cells, and a decrease in the repulsion response of EphB2 cells. SHIP2 knockdown in ephrinB1 cells also decreases their repulsion response, but does not disrupt segregation which is largely driven by forward signaling. These findings show that activation of EphB2 leads to recruitment and phosphorylation of SHIP2, and that SHIP2 contributes to cell repulsion responses that underlie cell segregation.

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The EphB6 Receptor: Kinase-Dead but Very Much Alive

International Journal of Molecular Sciences ◽

10.3390/ijms22158211 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8211

Author(s):

Timothy G. Strozen ◽

Jessica C. Sharpe ◽

Evelyn D. Harris ◽

Maruti Uppalapati ◽

Behzad M. Toosi

Keyword(s):

Signal Transduction ◽

Molecular Mechanisms ◽

Biological Effects ◽

Adaptor Proteins ◽

Molecular Switch ◽

Comparative Approach ◽

Eph Receptors ◽

Eph Receptor ◽

Sam Domain ◽

Receptor Clusters

The Eph receptor tyrosine kinase member EphB6 is a pseudokinase, and similar to other pseudoenzymes has not attracted an equivalent amount of interest as its enzymatically-active counterparts. However, a greater appreciation for the role pseudoenzymes perform in expanding the repertoire of signals generated by signal transduction systems has fostered more interest in the field. EphB6 acts as a molecular switch that is capable of modulating the signal transduction output of Eph receptor clusters. Although the biological effects of EphB6 activity are well defined, the molecular mechanisms of EphB6 function remain enigmatic. In this review, we use a comparative approach to postulate how EphB6 acts as a scaffold to recruit adaptor proteins to an Eph receptor cluster and how this function is regulated. We suggest that the evolutionary repurposing of EphB6 into a kinase-independent molecular switch in mammals has involved repurposing the kinase activation loop into an SH3 domain-binding site. In addition, we suggest that EphB6 employs the same SAM domain linker and juxtamembrane domain allosteric regulatory mechanisms that are used in kinase-positive Eph receptors to regulate its scaffold function. As a result, although kinase-dead, EphB6 remains a strategically active component of Eph receptor signaling.

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Investigation of ferroelectrics using conventional and in situ electron microscopy

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100170669 ◽

1994 ◽

Vol 52 ◽

pp. 586-587

Author(s):

V. Saikumar ◽

H. M. Chan ◽

M. P. Harmer

Keyword(s):

Nonvolatile Memory ◽

Ferroelectric Materials ◽

Gate Insulator ◽

Sensors And Actuators ◽

In Situ Electron Microscopy ◽

Ferroelectric Domains ◽

Domain Boundaries ◽

Domain Interactions ◽

Memory Applications

In recent years, there has been a growing interest in the application of ferroelectric thin films for nonvolatile memory applications and as a gate insulator in DRAM structures. In addition, bulk ferroelectric materials are also widely used as components in electronic circuits and find numerous applications in sensors and actuators. To a large extent, the performance of ferroelectric materials are governed by the ferroelectric domains (with dimensions in the micron to sub-micron range) and the switching of domains in the presence of an applied field. Conventional TEM studies of ferroelectric domains structures, in conjunction with in-situ studies of the domain interactions can aid in explaining the behavior of ferroelectric materials, while providing some answers to the mechanisms and processes that influence the performance of ferroelectric materials. A few examples from bulk and thin film ferroelectric materials studied using the TEM are discussed below.Figure 1 shows micrographs of ferroelectric domains obtained from undoped and Fe-doped BaTiO3 single crystals. The domain boundaries have been identified as 90° domains with the boundaries parallel to <011>.

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